Uprima® 2 mg, 3 mg     PRODUCT NAME Apomorphine HCl Sublingual Trade Name Uprima ® , Taluvian DESCRIPTION Apomorphine is a dopaminergic agonist with affinity for both D1 like and D2 like receptors in sites within the brain known to be involved in the mediation of erection. Apomorphine hydrochloride (HCl) is chemically designated 4H-dibenzo [de, g] quinoline-10, 11-diol, 5, 6, 6a, 7-tetrahydro-6-methyl-, hydrochloride, hemihydrate, (R) - or (6a, R)-5, 6, 6a, 7-tetrahydro-6-methyl-4H-dibenzo [de, g] quinoline-10, 11-diol, hydrochloride, hemihydrate. Its molecular formula is C17 H17 NO2 o HCl o 1/2 H2 0 and molecular weight is 312.8. Apomorphine HCl has the following structure: Apomorphine HCl is a white to greyish minute glistening crystal or powder and melts with decomposition between 225°C and 236°C. Apomorphine HCl is soluble in alcohol and chloroform and slightly soluble in water (1 gram in 50 mL). Apomorphine has no narcotic pharmacological similarity to opiates. Apomorphine HCl tablets are available in two dosage strengths, each administered as a sublingual (SL) tablet. Each tablet contains 2 or 3 mg apomorphine HCl, microcrystalline cellulose, hydroxypropylmethylcellulose, citric acid, magnesium stearate, ascorbic acid, edetate disodium dihydrate, colloidal silicon dioxide, ferric oxide, acesulfame potassium, orange mint flavor and a sufficient amount of mannitol to attain final tablet weight. CLINICAL PHARMACOLOGY Apomorphine is a dopaminergic agonist with affinity for both D1 and D2 receptors in sites within the brain known to be involved in the mediation of erection. Studies in vivo have shown the erectile function effects of apomorphine are mediated at dopamine receptors in various nuclei in the hypothalamus and midbrain. In par-ticular, the paraventricular nucleus of the hypothalamus has been identified as the site of action. This site may mediate autonomic aspects of sexual arousal. Oxytocinergic and nitric oxide signaling may be involved in the cascade of neural events that result from the central action of apomorphine. Apomorphine acts as a central initiator of erection and enhances pro-erectile stimuli. The erectogenic effects of apomorphine arise from improved central neural signaling specific to penile vascular response. Pharmacokinetics Following sublingual administration, apomorphine is rapidly absorbed, reaching peak plasma concentrations within 40-60 minutes. Apomorphine is rapidly cleared from plasma, having an apparent terminal elimination half-life of approximately three hours. Due to extensive first pass metabolism, apomorphine HCl appears to be nearly ineffective when swallowed, with only 1 to 2% of the activity seen after intravenous or subcutaneous administration. Absorption Apomorphine is rapidly absorbed from the sublingual cavity and can be detected in plasma within ten minutes after placing the tablet under the tongue. Peak plasma concentrations are attained within 40 to 60 minutes. Increasing the dosage strengths of apomorphine sublingual tablets provides dose proportional increases on Cmax and AUC . The bioavailability of apomorphine sublingual tablets, relative to subcutaneous administration, is approximately 17% to 18%. Due to the sublingual route of administration, the effect of food on the absorp-tion of apomorphine does not require investigation. Distribution Apomorphine is approximately 90% bound to plasma proteins, primarily albumin. Protein binding is indepen-dent of concentration between 1.0 and 1000 ng/mL, which exceeds the concentration range achieved with the recommended doses. Apomorphine readily penetrates into blood cells, with a blood/plasma ratio of about one. Metabolism Apomorphine is extensively metabolized, primarily through conjugation with glucuronic acid or sulfate. Apomorphine is also metabolized by N-demethylation, leading to the formation of norapomorphine, which is converted to glucuronide and sulfate conjugates. The major metabolite in plasma of subjects receiving a sin-gle sublingual dose of apomorphine is apomorphine sulfate. The glucuronides of apomorphine and norapo-morphine are found in plasma at lower concentrations. These conjugates are not expected to be pharmacolog-ically active. In vitro studies suggest that apomorphine HCl SL at recommended doses, is not likely to inhibit the metabolism of other drugs by cytochrome P450 isoforms CYP1A2, 3A4, 2C9, 2C19 or 2D6. Elimination Following a 2 mg sublingual dose of [14 C ] apomorphine HCl, radioactivity was eliminated in both urine (93%) and feces (16%). Less than 2% of the apomorphine dose was excreted in urine as free apomorphine. About 59% of the dose was excreted as apomorphine sulfate, 12% as apomorphine glucuronides and 18% as norapomorphine and its conjugates. Apomorphine, norapomorphine, and their sulfates were found in feces. Special Populations Elderly: The pharmacokinetics of apomorphine HCl 5 mg sublingual tablets were investigated in healthy male subjects older than 65 years. The tmax was 36% longer and Cmax was 21% lower in elderly subjects than in young subjects. The AUC was 11% larger in the elderly. Results from this study showed that no dose adjust-ment is necessary with the elderly. (See Dosage and Administration section.) Pediatric: The pharmacokinetics of apomorphine HCl SL has not been studied in subjects/ patients younger than 18 years. Gender: The pharmacokinetics of apomorphine HCl SL in females has not been investigated. Renal Insufficiency: The pharmacokinetics of apomorphine HCl 5 mg SL were studied in subjects with varying degrees of renal function. AUC was increased by 4% in subjects with mild (Clcr = 40 to 80 mL/min/1.73 m 2 ), 52% in subjects with moderate (Clcr = 10 to 40 mL/min/1.73 m 2 ) and 67% in subjects with severe (Clcr < 10 mL/min/1.73 m 2 ) renal impairment. Cmax was affected little by renal impairment. The apparent terminal elimina-tion half-life of apomorphine was predicted to increase by 0.24 hour with each 10 mL/min/1.73 m 2 decrease in creatinine clearance. Plasma protein binding of apomorphine HCl was not affected by renal impairment. The effect of hemodialysis on apomorphine pharmacokinetics has not been studied. The maximum dosage should therefore be limited to 2 mg in patients with severely impaired renal function. Hepatic Insufficiency: The pharmacokinetics of apomorphine HCl 2 and 4 mg SL were studied in subjects with mild, moderate, or severe hepatic impairment based on the Child-Pugh classification. Mean Cmax was 16 to 62% higher and mean AUC was 35 to 68% higher in subjects with varying degrees of hepatic impairment than in sub-jects with normal hepatic function. The apparent terminal elimination half-life of apomorphine HCl 2 mg SL was 1.8 to 3.5 hours in subjects with hepatic impairment compared with 1.9 hours in subjects with normal hepatic function. Plasma protein binding of apomorphine HCl was not consistently affected by hepatic impairment. Based on the increase in Cmax , patients with significant hepatic impairment should be administered apomorphine HCl SL only when the benefit outweighs the risk. Care should be exercised for any dose above 2 mg. INDICATIONS AND USAGE Apomorphine HCl SL is indicated for the treatment of erectile dysfunction , which is the inability to achieve or maintain a penile erection sufficient for satisfactory sexual performance. In order for apomorphine HCl SL to be effective, sexual stimulation is required. Apomorphine HCl SL is not indicated for use by women. CONTRAINDICATIONS Apomorphine HCl SL is contraindicated in patients with: 1. Known hypersensitivity to apomorphine or any of the excipients in the sublingual tablet formulation, or; 2. Severe unstable angina, recent myocardial infarction, severe heart failure or hypotension and other conditions where sexual activity is inadvisable. WARNINGS Apomorphine HCl SL may produce a vasovagal autonomic syndrome that can manifest as a brief self-limiting decrease in blood pressure and cause fainting/syncope (incidence <0.2% at the recommended dose regimen). Virtually all cases have occurred within the first two hours of administration. The majority of cases have occurred after the first apomorphine HCl SL dose or following an increase in dose. No subsequent fainting episodes were reported in patients who had experienced syncope and continued apomorphine HCl SL use. There is no evidence that apomorphine HCl SL causes sustained blood pressure changes. Nearly all (>90%) of synco-pal episodes were preceded by a prodrome of symptoms that included one or more of the following: moderate to severe nausea, vomiting, pallor, sweating/hot flashes (diaphoresis), and/or dizziness/lightheadedness (see Adverse Reactions section). If patients experience any of the prodromal symptoms listed above, they should not attempt to stand-up, but should lie down and raise their legs until their symptoms resolve. Each patient should be instructed to then contact their physician prior to taking another dose. Studies on the effects on the ability to drive and use machines have not been performed. Because some patients can experience dizziness, lightheadedness, and uncommonly, syncope, they should not engage in activities such as driving or operating machinery for at least two hours after administration of apomorphine HCl SL or until any such symptoms are fully resolved. PRECAUTIONS Apomorphine HCl SL should be used with caution in patients with uncontrolled hypertension, known hypoten-sion or with a history of postural hypotension. Acute decreases in blood pressure have been noted after apomor-phine HCl SL administration. Elderly patients may be prone to such occurrences and are more susceptible to any deleterious consequences. Apomorphine HCl SL should be used with caution in patients taking antihypertensives or nitrate medications due to the potential for hypotension. Apomorphine HCl SL should be used with caution in patients with compromised renal or hepatic function. Agents for the treatment of erectile dysfunction should be used with caution in patients with anatomical penile deformity (such as angulation, cavernosal fibrosis, or Peyronie's disease). The safety and efficacy of apomorphine HCl SL use with other treatments for erectile dysfunction have not been studied. Therefore, the use of such combination is not recommended. Drug Interactions In vitro studies with human liver microsomes indicated that high concentrations of apomorphine inhibit the activity of CYP1A2, CYP3A4 and CYP2D6. However, Cmax values (approximately 1 ng/mL) from a 4-mg sublin-gual dose of apomorphine were at least 1000-fold lower than the K i values for CYP1A2, CYP3A4 and CYP2D6 activity. These data suggest that apomorphine, at the recommended doses, is not likely to inhibit the metabolism of other drugs by these CYP isoforms. Significant inhibition of CYP2C9 or CYP2C19 activity was not observed in the in vitro studies at apomorphine concentrations up to 100 µM. In vitro studies demonstrated the involvement of several P450 isoforms, primarily CYP1A2, CYP3A4 and CYP2C19, in the N-demethylation of apomorphine. Since apomorphine is also metabolized by sulfation and glu-curonidation, other compounds that inhibit or induce cytochrome P450 are not expected to affect the pharmaco-kinetics of apomorphine. Interactions between apomorphine HCl SL tablets and antihypertensives (angiotensin- converting enzyme (ACE) inhibitors, ß-blockers, calcium channel blockers and alpha 1 blockers) have been studied. The only significant findings were in the group of patients who were taking nitrates. A proportion (4/40) of these patients experi-enced vasovagal symptoms and significant standing blood pressure decreases when apomorphine HCl SL was administered at higher than the recommended dose (5 mg). It is therefore recommended that caution be observed when apomorphine HCl SL is administered in combination with nitrates. Interaction studies and/or clinical experience with ondansetron hydrochloride, prochlorperazine maleate and domperidome indicate that these agents may be given safely with apomorphine HCl SL. No studies have been performed with apomorphine HCl SL in combination with other antiemetics, hence other combinations are not recommended. Apomorphine HCl SL should not be given in combination with other centrally-acting dopamine agonists or antagonists because of the potential for pharmacodynamic interactions. No formal drug interaction studies have been performed with other agents for erectile dysfunction, antidepres-sants, anticonvulsants or other CNS-active agents, however clinical experience has not indicated the presence of interactions. Interaction studies in volunteers where alcohol was given with apomorphine HCl SL indicated that concurrent alcohol intake may cause an increase in the incidence and extent of hypotension. Additionally, intake of alcohol can diminish sexual performance. Carcinogenesis, Mutagenesis and Impairment of Fertility Long-term carcinogenicity studies in male and female rats were performed. Subcutaneous doses of 0.1, 0.3 and 0.8 mg/kg/day (up to 69-times the clinical plasma level based on AUC ) were administered to male rats for 97 weeks and resulted in an increase in the incidence of interstitial testicular Leydig cell tumors. These tumors were only sta-tistically significant at the highest dose of 0.8 mg/kg/day and occurred secondary to alteration of hormonal home-ostasis. This finding is of no clinical significance since the endocrine mechanisms believed to be involved in the production of Leydig cell adenoma in rats are not relevant to humans. Female rats doses with 0.1, 0.3, 0.8 and 2.0 mg/kg/day (at more than 140 times the clinical plasma levels following a 4 mg dose, based on the AUC value) for 96 weeks did not have any apomorphine related increase in tumors. A six month study was performed in the p53+/- knockout transgenic mouse model. This model is considered highly sensitive to genotoxic carcinogens. Doses used in male and female mice were up to 20 and 40 mg/kg/day, respec-tively. These doses produced up to 492 and 787-times the clinical plasma levels (compared to a human dose of 4 mg). There was no drug-related increase in tumor incidence. The following battery of mutagenicity assays were performed: in vitro mouse lymphoma test, in vitro cytogenetics in Chinese Hamster Ovary cells (CHO), in vivo mouse bone marrow micronucleus test and in vivo rat hepatocyte unscheduled DNA synthesis (UDS) assay. Positive responses were observed in the mouse lymphoma and the CHO tests. These positive results were reduced or eliminated by supplementing with the antioxidant glutathione. Absence of glutathione in vivo is uncommon except in cases of severe compromise of metabolic enzymes of the liver. In summary, the genotoxic potential demonstrated in the absence of glutathione was negated by consistent negative results using a genotoxic sensitive model in vivo for six months (i.e., p53+/- knockout), and in all other in vivo tests. In a male rat reproductive study, a dose of 2 mg/kg/day (83 times the clinical plasma level) did not alter spermato-genesis or fertility, and had no adverse effect on male reproduction. In summary, preclinical data revealed no special hazard for humans based on conventional studies of safety phar-macology, repeated dose toxicity, genotoxicity and carcinogenicity. Apomorphine has no effect on fertility in male rats. Findings observed in animals included behavioral disorders, retinal atrophy, Leydig cell tumors, and hemato-logical changes. All of these events occurred at exposure levels much higher than those used in clinical trials, were species-specific, and they are not considered relevant to the clinical use of apomorphine HCl SL. Pregnancy, Nursing Mothers and Pediatric Usage Apomorphine HCl SL tablets are not indicated for use in newborns, children or women. Animal reproduction studies have not been conducted with apomorphine HCl SL tablets. It is not known whether apomorphine HCl SL tablets can cause fetal harm in pregnant woman or whether it can affect female reproduction capacity. Also, it is not known whether apomorphine HCl passes into breast milk. ADVERSE REACTIONS More than 4000 men have received apomorphine HCl 2 to 6 mg SL tablets in clinical trials. Patients who had at least one dose of apomorphine HCl SL 2 mg or 3 mg in Phase II/III studies were of varying ages with a diagnosis of organic, psychogenic or mixed erectile dysfunction, including hypertensive patients (35%), diabetic patients (16%), patients with benign prostatic hyperplasia (21%) and patients with coronary artery disease (13%) as evi-denced by a history of angina, coronary artery bypass surgery, angioplasty or myocardial infarction. Adverse events associated with apomorphine HCl SL were generally dose related, mild and transient. Adverse events were considered tolerable at recommended doses. Apomorphine HCl SL may produce an autonomic syndrome (vasovagal in origin) that can lead to a brief, self-limit-ing decrease in blood pressure that can cause fainting/syncope (incidence <0.2% at the recommended dose regi-men). (See WARNINGS Section.) Patients who had a history of hypertension, coronary artery disease and diabetes who were taking one or more concomitant medications (i.e., nitrates, antihypertensives) were included in clinical trials. Adverse events and their frequency in this patient population were similar to that seen in the general population. In multicenter Phase III studies, the following treatment-emergent adverse events were noted in >1% of patients taking the recommended doses. Table 1. Treatment-emergent adverse events reported by > 1.0% of patients taking 2 to 3 mg apomorphine Body System 2 to 3 mgn=1378   No. (%) Body as a whole   Headache 93 (6.7) Pain 24 (1.7) Infection 25L (1.8) Cardiovascular system   Vasodilatation (Flushing) 19 (1.4) Digestive system   Nausea 94 (6.8) Nervous system   Dizziness 60 (4.4) Somnolence 26 (1.9) Respiratory system   Pharyngitis 30 (2.2) Rhinitis 38 (2.8) Increased Cough 20 (1.5) Yawn 27 (2.0) Skin and Appendages   Sweating 17 (1.2) Special senses   Taste Disturbance 18 (1.3) At doses higher than recommended, adverse events were similar to these, but generally were reported more fre-quently. The treatment related adverse events in the long-term studies were similar to those seen in the controlled clinical studies. Nine hundred ninety-five patients (995) took their first dose of apomorphine HCl SL tablets at home. The reported adverse events were generally similar to those observed during both the long- and short-term studies. Special Populations Patients with impaired renal or hepatic functions, spinal cord injury, prostatectomy, hypertension, and diabetes were included in the studies. The treatment-emergent adverse events were similar in type and incidence to those seen in other clinical trials. Laboratory No consistent laboratory abnormalities have been noted. The following sporadic laboratory abnormalities were observed in a few patients: abnormal ECG including ventricular extrasystoles, abnormal liver function tests, albuminuria, hematuria, hyperc-holesterolemia, hyperglycemia, hyperkalemia, hyperlipidemia, hypokalemia, hypoglycemia, increased uric acid level, and leukocytosis. OVERDOSAGE Overdosage has not been reported in any of the apomorphine HCl SL clinical trials. Apomorphine HCl SL in high doses may induce vomiting. If the tablets are swallowed the absorption of apomorphine will be reduced by first pass metabolism. There is no specific antidote available for apomorphine HCl SL tablets. Therefore, treatment should be supportive and symptomatic. It is advised that vital signs such as blood pressure and heart rate are monitored. Measures to avoid possible orthostatic hypotension should be taken. The use of a dopamine antagonist may be considered. DOSAGE AND ADMINISTRATION The patient should drink a small amount of water before taking apomorphine HCl SL to optimize the dissolution of the tablet. One tablet of apomorphine HCl SL should be placed under the tongue approximately 20 minutes prior to sexual activity. In the majority of patients the tablet will be completely dissolved within ten minutes. If any residual amount remains in the mouth after 20 minutes it may be swallowed. In order for apomorphine HCl SL to be effective, sexual stimulation is required. The patient should initiate sexual activity and proceed to intercourse when he feels ready. The median onset of effect is approximately 18 to19 minutes after the tablet is placed under the tongue. The onset time varies from patient to patient. Initial Dose The recommended starting dose of apomorphine HCl SL tablets is 2 mg for all patients. Subsequent Doses If necessary, the dose should be increased to a maximal dose of 3 mg. The patient's dose should be adjusted to a dose that is sufficient for sexual intercourse. A minimum of eight hours should be allowed to elapse prior to administering a subsequent dose. HOW SUPPLIED Apomorphine HCl SL tablets are available in the following two dosage strengths: Dosage Strength Shape Product ID 2 mg Pentagon brick red tablets embossed with and 2 on opposite side of tablet 3 mg Triangle brick red tablets embossed with and 3 on opposite side of tablet List No. W108, W109 The tablets are available in foil-foil blister packs. Storage and Handling Apomorphine HCl SL tablets should be stored below 25°C (77°F). Do not freeze. Protect from light and moisture. Store in original package. The shelf life of Apomorphine HCI SL Tablets is 24 months from the date of manufacture.