UPRIMA SL
Apomorphine HCl
2mg apomorphine hydrochloride (as the hemihydrate) Ph. Eur. sublingual tablets
3mg apomorphine hydrochloride (as the hemihydrate) Ph. Eur. sublingual tablets
Presentation
UPRIMA® 2mg sublingual tablets (SL) are pentagon shaped tablets embossed with 2 on one face and TAP on the other.
UPRIMA® 3mg sublingual tablets (SL) are triangle shaped tablets embossed with 3 on one face and TAP on the other.
Each tablet contains 2 or 3 mg apomorphine HCl hemihydrate, Ph. Eur., and the following non-active excipients: microcrystalline cellulose, hydroxypropylmethylcellulose, citric acid, magnesium stearate, ascorbic acid, edetate disodium dihydrate, colloidal silicon dioxide, ferric oxide, acesulfame potassium, orange mint flavour and a sufficient amount of mannitol to attain the final tablet weight.
Uses
Actions
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 particular, 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 signalling 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 signalling 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 2-3 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. Mean Cmax values from the 2 mg and 4 mg apomorphine HCl sublingual tablet was 0.70 ng/mL; mean AUC ¥ value was 1.23. The coefficients of the intersubject variability were approximately 40% to 70%.
Absorption
Apomorphine is rapidly absorbed from the sublingual cavity and can be detected in plasma within 10 minutes after placing the tablet under the tongue. Peak plasma concentrations are attained within 40 to 60 minutes. Increasing the dosage strengths of apomorphine HCl sublingual tablets provides dose proportional increases on Cmax and AUC ¥. The bioavailability of apomorphine, sublingual tablet strengths relative to subcutaneous administration, is approximately 17%. Due to the sublingual route of administration, the effect of food on the absorption of apomorphine does not require investigation.
Distribution
Apomorphine is approximately 90% bound to plasma proteins, primarily albumin. Protein binding is independent 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 1.
Metabolism
Apomorphine is extensively metabolised, primarily through conjugation with glucuronic acid or sulphate. Apomorphine is also metabolised by N -demethylation, leading to the formation of norapomorphine, which is converted to glucuronide and sulphate conjugates. The major metabolite in plasma of subjects receiving a single sublingual dose of apomorphine is apomorphine sulphate. The glucuronides of apomorphine and norapomorphine are found in plasma at lower concentrations. These conjugates are not expected to be pharmacologically active. In vitro studies suggested that Uprima 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 [14C] apomorphine HCl, radioactivity was eliminated in both urine (93%) and faeces (16%). Less than 2% of the apomorphine dose was excreted in urine as free apomorphine. About 59% of the dose was excreted as apomorphine sulphate, 12% as apomorphine glucuronides and 18% as norapomorphine and its conjugates. Apomorphine, norapomorphine, and their sulphates were found in faeces.
Special Populations
The patient population analysed in the apomorphine SL trials is generally reflective of the ED population at large. Among the 3777 patients (all males) in Phase II/III studies who took at least one dose of apomorphine SL, 88% were Caucasian and the mean age was 56 years (range, 21-78 years). Sixteen percent (17%) were tobacco users, 63% periodically consumed alcohol, 18% were diabetics, 35% had hypertension, 14% had a history of coronary artery disease and 20% had benign prostatic hyperplasia (BPH). Patients with symptomatic hypotension, significantly abnormal ECG findings or uncontrolled hypertension were excluded.
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 adjustment is necessary with the elderly. (See DOSAGE AND ADMINISTRATION section.)
Paediatric: 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 = 40-80 mL/min/1.73 m2), 52% in subjects with moderate (Clcr = 10-40 mL/min/1.73 m2) and 67% in subjects with severe (Clcr ≤ 10 mL/min/1.73 m2) renal impairment. The Cmax was affected little by renal impairment. The apparent terminal elimination half-life of apomorphine was predicted to increase by 0.24 hour with each 10 mL/min/1.73 m2 decrease in creatinine clearance. Plasma protein binding of apomorphine HCl was not affected by renal impairment. The effect of haemodialysis on apomorphine pharmacokinetics has not been studied. Since Cmax was affected little by renal impairment, it was concluded that patients with impaired renal function may initiate dosing with apomorphine HCl SL at 2 mg. Care should be exercised in any dose increase. (See DOSAGE AND ADMINISTRATION section.)
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 subjects 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 2mg.
Indications
UPRIMA® SL tablets are indicated for the treatment of erectile dysfunction.
Dosage and Administration
UPRIMA SL tablets are available in two dosage strengths: 2 and 3mg.
Drink enough water to moisten your mouth just before taking an UPRIMA SL tablet.
Approximately 20 minutes prior to sexual activity, place one UPRIMA SL tablet under the tongue.
The tablet should dissolve under the tongue and should not be swallowed.
In the majority of patients the tablet will be completely dissolved within 10 minutes.
If any residual amount remains in the mouth after 20 minutes it may be swallowed.
In order for Uprima 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 to 19 minutes after the tablet is placed under the tongue. The onset time varies from patient to patient.
Initial Dose
The recommended starting dose of UPRIMA 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.
Contraindications
The use of UPRIMA SL tablets (apomorphine HCl) is contraindicated in patients with:
Known hypersensitivity to, apomorphine or any of the excipients in the sublingual tablet formulation or;
Severe unstable angina, recent myocardial infarction, severe heart failure or hypotension and other conditions where sexual activity is inadvisable.
Warnings and Precautions
Warnings
Apomorphine HCl SL may produce a vasovagal autonomic syndrome that may 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 syncopal 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/light-headedness (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 Uprima or until any such symptoms are fully resolved.
Interactions between apomorphine HCl SL tablets and antihypertensives (angiotension- converting enzyme (ACE) inhibitors, β-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 in combination with multiple cardiovascular medications. A small proportion of these patients experienced 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 administering apomorphine HCl SL to patients taking nitrates.
In alcohol interaction studies, healthy subjects were administered higher than recommended doses of apomorphine HCl SL tablets (6 mg) approximately 30 minutes after ingesting the ethanol beverage. Ingestion of an ethanol (0.3 g/kg) beverage had little, if any, effect on either the bioavailability of apomorphine from apomorphine HCl 6 mg SL tablets or blood pressure. However, ingestion of a larger amount of ethanol (0.6 g/kg) one-half-hour before apomorphine HCl SL (6 mg) dosing increased apomorphine Cmax by approximately 23% and the AUC ¥ by 12% and resulted in significant reductions in mean systolic and diastolic blood pressure (10 to 16 mmHg) at 45 minutes post dosing. In addition, the following adverse events were increased in frequency: dizziness, hypotension, nausea and pallor. Administration of apomorphine HCl 6 mg SL tablets resulted in a slight (8% to 12%) but statistically significant decrease in the bioavailability of ethanol from a 0.3 g/kg or 0.6 g/kg dose of alcohol. In a 70 kg (154 lb) man, 0.6 g/kg of ethanol equals approximately five 30mL shots or 3.3 360mL beers or 2.5 180mL glasses of wine.
Interaction studies in volunteers where alcohol was given with Uprima indicated that concurrent alcohol intake may cause an increase in the incidence and extent of hypotension. Additionally, intake of alcohol can diminish sexual performance.
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.
Precautions
Uprima should be used with caution in patients with uncontrolled hypertension, known hypotension or with a history of postural hypotension. Acute decreases in blood pressure have been noted after Uprima administration. Elderly patients may be prone to such occurrences and are more susceptible to any deleterious consequences.
Uprima should be used with caution in patients taking antihypertensives or nitrate medications due to the potential for hypotension.
Uprima 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 efficacy of Uprima in patients with spinal cord injury, multiple sclerosis and radical prostatectomy has not been assessed.
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.
Couples using UPRIMA SL tablets should employ adequate and appropriate contraception if the partner is of childbearing potential or is breastfeeding. There is no information on the effects of apomorphine that may be transferred to the partner.
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 tumours. These tumours were only statistically significant at the highest dose of 0.8 mg/kg/day and occurred secondary to alteration of hormonal homeostasis. 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 tumours.
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, respectively. 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 tumour 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 (ie. 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 spermatogenesis or fertility, and had no adverse effect on male reproduction.
Pregnancy, Nursing Mothers and Paediatric Usage
UPRIMA SL tablets are not indicated for use in newborns, children or women.
A decrease in the number of pregnant animals has been observed in a rat fertility study where untreated female rats were mated with male rats given 2mg/kg/day apomorphine SC. No effect on fertility or spermatogenesis was observed in male rats treated with apomorphine SC at doses up to 0.8 mg/kg/day (associated with plasma concentrations (AUC) about 80 times greater than those expected in humans after a single 4 mg dose of Uprima). Effects on female fertility have not been determined; apomorphine is not proposed for use in females.
It is not known whether apomorphine HCl passes into breast milk.
Adverse Effects
More than 4000 men have received apomorphine HCl 2mg to 6 mg SL tablets in clinical trials. Patients who had at least one dose of Uprima 2mg or 3mg 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 evidenced by a history of angina, coronary artery bypass, 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-limiting decrease in blood pressure that can cause fainting/syncope (incidence <0.2% at the recommended dose regimen). (See WARNINGS )
Patients who had a history of hypertension, coronary artery disease and diabetes who were taking one or more concomitant medications (ie., 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 multicentre 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 3mg apomorphine
|
Body System |
2 to 3 mg
n = 1378 |
| |
No. |
% |
|
Body as a whole |
|
|
|
Headache |
93 |
6.7 |
|
Pain |
24 |
1.7 |
|
Infection |
25 |
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 |
|
Taste senses |
|
|
|
Taste Disturbance |
18 |
1.3 |
At doses higher than recommended, adverse events were similar to these, but generally were reported more frequently.
The treatment related adverse events in the long-term studies were similar to those seen in the controlled clinical studies.
Nine hundred and ninety-five patients (995) took their first dose of Uprima tablets 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 studies. The treatment-emergent adverse events were similar in type and incidence to those seen in other clinical trials.
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 the 4-mg sublingual dose of apomorphine were at least 1000-fold lower than the Ki 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 ?M.
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 metabolised by sulphation and glucuronidation, other compounds that inhibit or induce cytochrome P450 are not expected to affect the pharmacokinetics of apomorphine.
Uprima 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, antidepressants, anticonvulsants or other CNS-active agents, however clinical experience has not indicated the presence of interactions.
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, haematuria, hypercholesterolaemia, hyperglycaemia, hyperkalemia, hyperlipidemia, hypokalemia, hypoglycaemia, 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.
Pharmaceutical Precautions
UPRIMA SL tablets should be stored below 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F). Protect from light and moisture.
The shelf life of UPRIMA( SL tablets from the date of manufacture, when stored in the original packaging is two years.
Medicine Classification
Prescription Only Medicine
Package Quantities
UPRIMA® SL 2mg tablets are available in aluminium foil blister packs containing, 1,2,3,4 or 8 tablets.
UPRIMA® SL 3mg tablets are available in aluminium foil blister packs containing, 1,2, 4, 8 or12 tablets.
Further Information
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 C17H17NO2 .HCl . 1/2 H20 and molecular weight is 312.8.
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 possesses no narcotic pharmacological similarity to the opiates.
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