Date of approval.
External
Rotigotine patch instructions
Please read the instructions carefully and use under the guidance of a physician
[Drug name]
Generic name: Rotigotine patch
Trade name: Upright (English: Neupro)
English name: Rotigotine Patches
Chinese Pinyin: Luotigaoting Tiepian
[Ingredients]
The main component of this product is rotikotine
Chemical name: (6S)-6-propyl[2-(2-thienyl)ethyl]amino-5,6,7,8-tetrahydro-1-naphthol
Chemical structure formula
Molecular formula: C19H25NOS
Molecular weight: 315.48
[Characteristic]
This product is a patch, including three parts: backing layer, protective layer and substrate. The protective layer is a transparent film with square rounded corners, the same size as the matrix and backing layer, divided into two parts by “S” shaped lines; the matrix is a white or off-white opaque adhesive without visible crystals; one side of the backing layer is beige to light brown, and the other side is completely covered by the matrix with square rounded corners.
Indications
This product is indicated for the monotherapy of early signs and symptoms of idiopathic Parkinson’s disease (not in combination with levodopa), or in combination with levodopa for all stages of the disease process until the late stage of the disease when the efficacy of levodopa decreases, becomes unstable or fluctuates (end-of-dose phenomenon or “switch” phenomenon).
Specification
(1) 4.5mg/10cm2 (release amount 2mg/24h)
(2) 9mg/20cm2 (drug release quantity 4mg/24h)
(3) 13.5mg/30cm2 (Release quantity 6mg/24h)
(4) 18mg/40cm2 (Release amount 8mg/24h)
Dosage and Administration
1. Usage
This product should be used once a day, at the same time every day. Keep this product on the skin for 24 hours, then replace a new patch on another part of the skin. If the patient forgets to replace the patch at the daily dosing time or the patch falls off, a new patch should be applied during the rest of the day.
2. Dosage
The recommended dosage is expressed in terms of the amount of drug release.
(1) The dose administered to patients with early Parkinson’s disease.
The starting dose is 2mg/24h, then increase 2mg/24h weekly until the effective dose, the maximum dose can be up to 8mg/24h.
The effective dose for some patients is 4 mg/24 h. The effective dose for most patients is 6 mg/24 h or 8 mg/24 h. This dose can be reached in 3 or 4 weeks. The maximum dose is 8mg/24h.
(2) Dosing for patients with advanced Parkinson’s disease with fluctuations.
The starting dose is 4mg/24h, and then the dose is increased by 2mg/24h every week until the effective dose, and the maximum dose can be up to 16mg/24h.
The effective dose for some patients is 4mg/24h or 6mg/24h. The effective dose for most patients is 8mg/24h, which can be achieved in 3 to 7 weeks. The maximum dose can be up to 16mg/24h.
If the dose is higher than 8mg/24h, multiple patches may be applied to achieve the final dose, for example, a combination of 6mg/24h and 4mg/24h patches may be applied to achieve a dose of 10mg/24h.
3. Discontinuation
This product should be discontinued gradually. The daily dose should be reduced by 2mg/24h every other day until it is completely discontinued (see [Precautions]).
4. Special groups
(1) Hepatic impairment: Patients with mild to moderate hepatic impairment do not require dose adjustment. Severe hepatic impairment may result in reduced clearance of rotigotine and should be applied with caution. Rotigotine has not been studied in this patient population. If hepatic impairment worsens, dose reduction may be required.
(2) Renal impairment: Dose adjustment is not required in patients with mild to severe renal impairment, including those requiring dialysis. Unintended accumulation of rotigotine levels may occur in acute renal failure (see [Pharmacokinetics]).
5. Method of Administration
This product is a transdermal patch. It should be applied to a clean, dry, intact, healthy skin surface on the abdomen, thighs, buttocks, flanks, shoulders, or upper arms. Avoid repeated application on the same area within 14 days. This product should not be applied to red, irritated or broken skin (see [Precautions]).
6. Use and handling
Each patch are individually packaged, and should be used immediately after opening the package. First remove half of the protective layer, the paste surface firmly adhered to the skin. Then fold the patch, remove the other half of the protective layer. Do not touch the paste surface of the patch. Use the palm of your hand to press the patch 20 to 30 seconds to ensure that the patch paste firmly. Do not divide the patch into small pieces to use.
Adverse reactions
1. Safety overview
According to the pooled analysis of placebo-controlled clinical trials, 72.5% and 58.0% of the 1307 patients treated with this product and 607 patients treated with placebo reported at least one adverse reaction, respectively. Dopaminergic adverse reactions, such as nausea and vomiting, may occur at the start of treatment. Upon continuation of treatment, these reactions were usually mild or moderate and transient in nature. Adverse reactions of nausea, vomiting, administration site reactions, drowsiness, dizziness and headache occurred in more than 10% of patients treated with this product. In the study, site rotation was performed as described in the drug insert. 35.7% of the 830 patients treated with the drug experienced site reactions, most of which were mild or moderate and limited to the site of administration. Only 4.3% of the subjects treated with this product discontinued treatment as a result.
2. List of Adverse Reactions
The following table lists all adverse reactions that occurred in the above clinical trials conducted in patients with Parkinson’s disease. Adverse reactions are listed by system organ under the corresponding frequency of occurrence (number of patients expected to have a reaction): very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/ 10,000); unknown (cannot be estimated from available data). Within each frequency group, adverse reactions are listed in descending order of severity.
List of adverse reactions
MedDRA Standard System Organ Classification Very common Common Uncommon Rare Unknown
Immune system abnormalities Hypersensitivity reactions, possibly including angioedema, tongue edema, and lip edema Mental system abnormalities Perceptual disordersa (including hallucinations, hallucinations, hallucinations, hallucinations, fantasies), insomnia, sleep disorders, nightmares, abnormal dreaming, impulse control disordersa,d (including pathological gambling, stereotypic/repetitive behavior, bulimia/eating disorderb, compulsive shoppingc) sleep episodes/sleep bursts, paranoia , sexual desire disordera (including hypersexuality, increased sexual desire), confused states of consciousness, disorientation disorderd, agitationd psychotic disorder, obsessive-compulsive disorder, aggressive behavior/aggressionb
Delusionsd, deliriumd dopamine dysregulation syndromec Neurological abnormalities Drowsiness, dizziness, headache Disorders of consciousness NECa (including syncope, vasovagal syncope, loss of consciousness), movement disorders, postural dizziness, drowsiness Convulsions Eye organ abnormalities Blurred vision, impaired vision, flash hallucinations Ear and vagus type abnormalities Vertigo Cardiac abnormalities Palpitations Atrial fibrillation Supraventricular tachycardia Abnormalities of blood vessels Upright Respiratory, thoracic and mediastinal abnormalities Hiccups Gastrointestinal abnormalities Nausea, vomiting Constipation, dry mouth, indigestion Abdominal pain Diarrheac Skin and subcutaneous tissue abnormalities Erythema, hyperhidrosis, pruritus Generalized pruritus, skin irritation, contact dermatitis Generalized rash Reproductive and breast abnormalities Erectile dysfunction Generalized abnormalities and site of administration abnormalities Site of administration reactionsa (including erythema, pruritus, pruritus, irritation, rash, dermatitis) irritation, rash, dermatitis, microvesicles, pain, eczema, inflammation, swelling, discoloration, papules, epidermal peeling, urticaria, hypersensitivity reactions) Peripheral edema, debilitating conditionsa (including fatigue, weakness, discomfort) Irritability Various tests Weight loss Elevated liver enzymes (including AST, ALT, GGT), weight gain, increased heart rate, elevated CPKd (see Special Populations) Injury, poisoning, and surgery Complications Falls a High term
b Reported in open studies
c Reported in post-marketing
d Reported in the 2011 double-blind, placebo-controlled study database
3. Description of specific adverse reactions
(1) Sleep bursts and drowsiness
Rotigotine can cause drowsiness (including excessive daytime sleepiness) and sleep attacks. In isolated cases, “sleep attacks” have occurred during driving and have resulted in motor vehicle accidents (see [Precautions]).
(2) Impulse control disorder
Pathological gambling, increased sexual desire, hypersexuality, compulsive spending or shopping, bulimia, and compulsive eating may occur in patients treated with dopamine agonists (including rotigotine) (see [Precautions]).
(3) Special populations
In clinical studies conducted in Japan, adverse events of elevated CPK were observed following the administration of rotigotine. In double-blind studies (patients with Parkinson’s disease and restless legs syndrome), its incidence in Japanese subjects was 3.4% in the rotigotine group and 1.9% in the placebo group. Most of the adverse events observed in all double-blind studies and open studies with elevated CPK have remitted and are mild in severity. CPK levels were not regularly monitored in other populations.
(4) Reports of suspected adverse reactions
The reporting of suspected adverse reactions is important after marketing approval of this product. This allows continuous monitoring of the benefit/risk ratio of this product. Health care professionals are required to report suspected adverse reactions through the appropriate reporting system.
(5) Overview of Safety in Chinese Subjects
A total of 247 subjects were randomized in a multicenter, randomized, double-blind, parallel, placebo-controlled clinical trial in Chinese subjects with early-onset idiopathic Parkinson’s disease (124 subjects received rotigotine and 123 subjects received placebo). A total of 134 subjects (54.3%) reported adverse reactions. The incidence of adverse reactions was comparable in the rotigotine and placebo groups, with 57.3% and 51.2% of subjects reporting at least one adverse reaction, respectively. Common adverse reactions such as nausea, vomiting, drowsiness, dizziness, erythema, and pruritus were reported in 5.6% to 8.9% in the rotigotine group and 1.6% to 5.7% in the placebo group. The majority of adverse reactions reported by subjects in the study were mild or moderate, with a reporting rate of 94.4% and 95.2% in the rotigotine and placebo groups, respectively.
In a multicenter, randomized, double-blind, parallel, placebo-controlled clinical trial in Chinese subjects with advanced idiopathic Parkinson’s disease, a total of 346 subjects were randomized (174 to rotigotine and 172 to placebo). A total of 189 subjects (54.6%) reported adverse reactions. The incidence of adverse reactions was slightly higher in the rotigotine group than in the placebo group, with 59.2% and 50.0% of subjects reporting at least one adverse reaction, respectively. Common adverse reactions such as nausea, dyskinesia, dizziness, and pruritus were reported in 6.3% to 10.9% in the rotigotine group and 1.2% to 5.8% in the placebo group. The majority of adverse reactions reported by subjects in the study were mild or moderate, with a reporting rate of 94.2% and 96.5% in the rotigotine and placebo groups, respectively.
Contraindications
Contraindicated in patients with hypersensitivity to the active ingredient or any of the excipients.
Contraindicated in persons undergoing magnetic resonance imaging or cardioversion (see [Precautions]).
[Precautions].
If patients with Parkinson’s disease who receive rotigotine have poor results, additional benefit may be obtained by switching to another dopamine agonist (see [Clinical Trials]).
1. Magnetic resonance imaging and cardioversion
The backing layer of this product contains aluminum. Patients should remove the patch when undergoing magnetic resonance imaging (MRI) or cardioversion to avoid skin burns.
2. Upright hypotension
Dopamine agonists are known to impair the systemic regulation of blood pressure, resulting in postural/erect hypotension. Such phenomena have been observed in rotigotine therapy, but their incidence is similar to that of the placebo-treated group. Since the overall risk of upright hypotension is associated with dopaminergic therapy, monitoring of blood pressure, especially at the start of treatment, is recommended.
3. Syncope
Syncope events have been observed in clinical trials with rotigotine, but their incidence was similar to that of the placebo-treated group. Because patients with cardiovascular disease have been excluded from this clinical trial, it is recommended that patients with severe cardiovascular disease be asked about syncope and aura symptoms.
4. Sleep spells and somnolence
Rotigotine can cause drowsiness and sleep attacks. Sleep attacks have been reported during daily activities, sometimes without any warning signs. The prescriber must continuously assess the patient for sleepiness or drowsiness, as sleepiness or drowsiness will only be acknowledged by direct questioning of the patient. Careful consideration should be given to the need for dose reduction or discontinuation.
5. Impulse control disorders
Patients should be monitored regularly for the occurrence of impulse control disorders. Patients and caregivers should be informed that treatment with dopamine agonists (including rotigotine) can cause behavioral symptoms of impulse control disorders, including pathological gambling, increased sexual desire, hypersexuality, compulsive spending or shopping, bulimia, and compulsive eating. If such symptoms occur, dose reduction/termination of treatment should be considered.
6. Nerve blocker malignant syndrome
Abrupt interruption of dopaminergic treatment can trigger symptoms of neuroblocker malignant syndrome. Therefore, a gradual reduction of the therapeutic dose is recommended (see [Dosage]).
7. Abnormal Thinking and Behavior
Abnormal thoughts and behaviors have been reported in a variety of forms, including paranoia, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggression, agitation, and delirium.
8. Complications of fibrosis
Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusions, pleural thickening, pericarditis, and cardiac valvulopathy have been reported in certain patients receiving ergocalcine dopaminergic therapy. These complications may resolve after discontinuation of the drug, but complete recovery is difficult. While these adverse reactions are thought to be related to the ergoline structure of the compound, it remains unknown whether non-ergotropic dopamine agonists also cause these complications.
9. Psychostimulants
Patients treated with dopamine agonists should not be treated with psychostimulants for antiemetics. (See [Drug Interactions]).
10. Eye examinations
Eye examinations are recommended at regular intervals or in the event of visual abnormalities.
11. Heat source use
External heat sources (excessive light, electric blankets and other heat sources, such as: sauna, hot water bath) should not be applied to the patch.
12. Drug administration site reactions
Skin reactions may occur at the site of administration, usually mild or moderate. It is recommended that the daily rotation of the drug site (for example: from the right side to the left side, from the upper body to the lower body). Avoid repeated applications to the same site within 14 days. If reactions at the site of administration persist for several days or are persistent, or worsen in severity and spread the skin reaction beyond the site of administration, the individual patient’s risk/benefit ratio should be assessed.
If a patient develops a rash or irritation with this product, direct sunlight should be avoided until the skin has healed, as sunlight exposure may cause a change in skin tone.
If systemic skin reactions (e.g., allergic rash, including erythema, maculopapular rash, papules, or pruritus) are observed in association with the use of this product, it should be discontinued.
13. Peripheral edema
A clinical study conducted in patients with Parkinson’s disease showed that the incidence of peripheral edema at 6 months was approximately 4% during an observation period of up to 36 months.
14. Sulfite allergy
This product contains sodium metabisulfite, a sulfite, which can trigger allergic reactions in some susceptible individuals, including allergic symptoms and life-threatening or less severe asthma attacks.
15. Dopaminergic adverse reactions
The incidence of some dopaminergic adverse reactions (e.g., hallucinations, dyskinesia, and peripheral edema) is elevated in patients with Parkinson’s disease who are co-administered with levodopa. This condition should be considered when prescribing rotigotine.
16. Effects on the ability to drive and operate machinery
Rotigotine may have a greater effect on the ability to drive and operate machinery.
Patients being treated with rotigotine who experience sleepiness and/or sleep spells should be advised not to drive or engage in activities (e.g., operating machinery) where they or others may be at risk of serious injury or death due to decreased alertness until such recurrent episodes and sleepiness have subsided (see also Drug Interactions).
17. Special precautions for disposal
This product still contains active ingredients after use. After removal, the used patch should be folded, paste face inward, so that the matrix is not exposed, placed in the original bag, and then discarded out of reach of children. Any used or unused patch should be disposed of or returned to the pharmacy in accordance with local requirements.
[Pregnant and lactating women medication]
1. Women of childbearing potential, female contraception
Women of childbearing potential should take effective contraceptive measures to prevent pregnancy during treatment with Rotigotine.
2. Pregnancy
There are no adequate data on the use of rotigotine in pregnant women. Animal studies have not suggested teratogenic effects in rats or rabbits. However, embryotoxicity has been observed in rats and mice at maternal toxicity dose levels (refer to [Pharmacology and Toxicology] preclinical safety data). The potential risk to humans is unknown. Rotigotine should not be used in pregnant women.
3. Lactation
Rotigotine decreases the secretion of human prolactin, which may inhibit lactation. Studies in rats have shown that rotigotine and/or its metabolites can be secreted into breast milk. Due to the lack of human data, the use of this product should be discontinued during lactation.
4. Fertility
For information on fertility studies, see [Pharmacology and Toxicology] Preclinical Safety Data.
Pediatric Use]
The safety and efficacy of rotigotine in pediatric and adolescent populations have not been established, and no data are available on this product in the pediatric population with Parkinson’s disease.
Geriatric Use]
In clinical studies of Parkinson’s disease, approximately 50% of patients treated with rotigotine were 65 years of age and older, and approximately 11% were 75 years of age and older. There were no overall differences in safety and efficacy in these patients compared to younger patients, and no differences were found between older and younger patients in other clinical experiences reported, but increased sensitivity to the drug in some older adults cannot be ruled out. There was no overall difference in plasma rotigotine levels in patients aged 65 – 80 years compared to younger patients when the same dose of rotigotine was used.
Drug Interactions]
Rotigotine is a dopamine receptor agonist. Dopamine antagonists such as psychostimulants (e.g., phenothiazines, butylphenols, thiophanes) or metoclopramide may reduce the efficacy of this product and should be avoided in combination. In patients who are using sedatives or other CNS depressants (e.g., benzodiazepines, antipsychotics, antidepressants) or who consume alcohol, superimposed effects may occur with the combination of rotigotine and caution is advised.
The combination of levodopa and carbidopa with rotigotine has no effect on the pharmacokinetics of rotigotine, and rotigotine has no effect on the pharmacokinetics of levodopa and carbidopa.
The coadministration of domperidone with rotigotine had no effect on the pharmacokinetics of rotigotine.
In healthy volunteers, omeprazole (CYP2C19 inhibitor) at a daily dose of 40 mg in combination with rotigotine had no effect on the pharmacokinetics or metabolism of rotigotine.
As with other dopamine receptor agonists, this product may exacerbate dopaminergic adverse effects of levodopa and may initiate and/or exacerbate known movement disorders.
Coadministration with rotigotine (3 mg/24h) does not affect the pharmacodynamics and pharmacokinetics of oral contraceptives (ethinylestradiol 0.03 mg, levonorgestrel 0.15 mg). Interactions with other types of hormonal contraceptives have not been studied in depth.
[Drug overdose].
1. Symptoms
The most likely adverse reactions associated with the pharmacodynamic profile of dopamine agonists include nausea, vomiting, hypotension, involuntary movements, hallucinations, confusion, convulsions, and other signs of central dopaminergic stimulation.
2. Treatment
There is no known antidote for dopamine agonist overdose. If an overdose is suspected, the patch should be removed immediately. After removal of the patch, absorption of the active substance ceases and the blood concentration of rotigotine decreases rapidly. Close monitoring of the patient, including heart rate, rhythm and blood pressure, is required.
Treatment of drug overdose may require systemic supportive measures to maintain vital signs. Dialysis may not be effective because it does not clear rotigotine.
If rotigotine is to be discontinued, it should be discontinued gradually to avoid the development of neuroblocker malignant syndrome.
Clinical Trials]
The effectiveness of rotigotine in treating the signs and symptoms of idiopathic Parkinson’s disease was evaluated in a global drug development program. The program consisted of four parallel, randomized, double-blind, placebo-controlled pivotal studies and three studies exploring specific aspects of Parkinson’s disease.
Two pivotal trials (SP512 Part I and SP513 Part I) investigated the effectiveness of rotigotine for the treatment of signs and symptoms of idiopathic Parkinson’s disease in patients not receiving dopamine agonist combination therapy, not receiving levodopa, or with a duration of prior levodopa treatment ≤ 6 months. The primary evaluation metrics were scores on the activities of daily living (ADL) section (Part II) and the motor examination section (Part III) of the Unified Parkinson’s Disease Rating Scale (UPDRS). Efficacy was determined based on the subject’s response to treatment, including response and absolute improvement in the total scores of the ADL and motor examination sections (UPDRS Part II + III).
For part I of the double-blind study SP512, 177 patients were treated with rotigotine and 96 patients received placebo. Patients were given a starting dose of 2 mg/24 h, which was increased by 2 mg/24 h weekly until the optimal dose of rotigotine was reached, up to a maximum of 6 mg/24 h. The optimal dose was maintained for 6 months in all treatment groups.
At the end of the maintenance period, the optimal dose for 91% of subjects in the rotigotine treatment group was the maximum recommended dose of 6 mg/24 h. Improvement in UPDRS scores of up to 20% was seen in 48% of subjects in the rotigotine treatment group and 19% in the placebo group (between-group difference 29%, CI 95% 18%; 39%, p<0.0001). The UPDRS score (part II + III) improved by a mean of -3.98 points (baseline value 29.9 points) in the rotigotine treatment group, while it worsened by 1.31 points (baseline value 30.0 points) in the placebo treatment group. The difference between groups was 5.28 points, which was statistically significant (p<0.0001).
In part I of the double-blind study SP513, 213 patients were treated with rotigotine, 227 patients with ropinirole and 117 patients with placebo. Patients were given a starting dose of 2 mg/24 h, which was increased by 2 mg/24 h weekly until the optimal dose of rotigotine was reached, with a maximum dose of 8 mg/24 h reached after 4 weeks. In the ropinirole-treated group, patients were titrated to the optimal dose, with a maximum dose of 24 mg/day reached after 13 weeks. The maintenance period of treatment for patients in all groups was 6 months.
At the end of the maintenance period, the optimal dose for 92% of subjects in the rotigotine treatment group was the maximum recommended dose of 8 mg/24 h. Subjects with a 20% improvement in UPDRS scores were 52% in the rotigotine treatment group, 68% in the ropinirole group, and 30% in the placebo group (21.7%, CI95% 11.1%; 32.4%, between the rotigotine and placebo groups). 38.4%, CI95% 28.1%; 48.6%, and 16.6%, CI95% 7.6%; 25.7%, between the ropinirole and placebo groups). The mean improvement in UPDRS score (part II + III) was 6.83 points (baseline value 33.2 points) in the rotenogliptin-treated group, 10.78 points (baseline value 32.2 points) in the ropinirole group, and 2.33 points (baseline value 31.3 points) in the placebo-treated group. The differences between the active treatment group and the placebo group were both statistically significant. The study did not confirm that rotigotine was not inferior to ropinirole.
A follow-up open international multicenter study (SP824) investigated the tolerability of direct replacement of ropinirole, pramipexole or cabergoline and its efficacy in subjects with idiopathic Parkinson’s disease. 116 patients replaced their previous oral medication with rotenogliptin at a maximum dose of up to 8 mg/24h, of whom 47 previously received ropinirole at a maximum dose of 9 mg/day 47 previously received pramipexole at a maximum dose of 2 mg/day, and 22 previously received cartegolide at a maximum dose of 3 mg/day. The study showed that a switch to rotigotine treatment was feasible, but patients required a slight adjustment in the dose administered (median 2 mg/24 h), with only 2 in the ropinirole group, 5 in the pramipexole group, and 4 in the cabergoline group requiring adjustment. uPDRS Part I-IV scores were improved. The safety was consistent with the results observed in previous studies.
In a randomized, open study (SP825) of patients with early Parkinson’s disease, 25 patients were randomized to the rotigotine treatment group and 26 to the ropinirole treatment group. The dose administered was adjusted to the optimal dose, or the maximum dose (8 mg/24h or 9 mg/day), respectively. Improvements in early morning motor function and sleep were observed in both groups. After 4 weeks of maintenance treatment, patients’ motor symptoms (UPDRS Part III) improved by 6.3 ± 1.3 points in the rotigotine treatment group and by 5.9 ± 1.3 points in the ropinirole treatment group. Patient sleep (PDSS) improved by 4.1 ± 13.8 points in the rotigotine group and by 2.5 ± 13.5 points in the ropinirole group. Safety was comparable between the two groups, except for site of administration reactions.
In studies SP824 and SP825, conducted after previous comparative trials, rotenogliptin and ropinirole were comparable in efficacy at the same dose.
The other two pivotal trials (SP650DB and SP515) were conducted in patients treated with levodopa in combination. The main evaluation metric was the reduction in “off” time (hours). Efficacy was determined based on the subjects’ response to treatment, including response and improvement in the absolute value of the “off” time.
In the double-blind study SP650DB, 113 patients received rotigotine at a maximum dose of 8 mg/24h, 109 patients received rotigotine at a maximum dose of 12 mg/24h, and 119 patients received placebo. Patients were given a starting dose of 4 mg/24h, which was increased by 2 mg/24h weekly until the optimal dose of rotigotine was reached. Patients in each group were maintained on their optimal dose for 6 months. At the end of the maintenance period, subjects with at least 30% improvement accounted for 57% and 55% in the rotigotine 8mg/24h and 12mg/24h groups, respectively, and 34% in the placebo group (difference between the rotigotine and placebo groups 22% and 21%, CI95% 10%; 35% and 8%; 33%, p<0.01, respectively). The mean “off” time was reduced by 2.7 and 2.1 hours in the rotigotine group, respectively, compared to 0.9 hours in the placebo group. The differences were statistically significant (p<0.001 and p=0.003, respectively).
In the double-blind study SP515, 201 patients were treated with rotigotine, 200 patients with pramipexole and 100 patients with placebo. The starting dose for patients in the rotigotine treatment group was 4 mg/24 h, which was increased by 2 mg/24 h weekly until the optimal dose of rotigotine, with a maximum dose of 16 mg/24 h. In the pramipexole treatment group, the dose used was 0.375 mg in the first week, 0.75 mg in the second week, and then increased by 0.75 mg weekly until the optimal dose, with a maximum dose of 4.5 mg/day. The maintenance period of treatment was 4 months in all groups of patients.
At the end of the maintenance period, subjects with at least 30% improvement accounted for 60% in the rotigotine group, 67% in the pramipexole group, and 35% in the placebo group (25% difference between the rotigotine and placebo groups, CI95% 13%; 36%, 32% difference between the pramipexole and placebo groups, CI95% 21%; 43%, difference between the pramipexole and rotigotine groups (7%, CI95% -2%; 17%). The mean “off” time was reduced by 2.5 hours, 2.8 hours and 0.9 hours in the rotigotine, pramipexole and placebo groups, respectively. The differences between the active treatment group and the placebo group were all statistically significant.
Another international multicenter, double-blind study (SP889) was conducted in 287 patients with early or advanced Parkinson’s disease with poorly controlled early morning motor symptoms. Of these patients, 81.5% received levodopa in combination. 190 patients received rotigotine and 97 patients received placebo. Patients were given a starting dose of 2 mg/24h, which was increased by 2 mg/24h weekly and adjusted to the optimal dose of rotigotine or placebo over 8 weeks, with a maximum dose of 16 mg/24h, followed by 4 weeks of maintenance treatment. The primary evaluation metrics were early morning motor function evaluated according to UPDRS Part III and nocturnal sleep disturbance evaluated according to the modified Parkinson’s Disease Sleep Scale (PDSS-2). At the end of the maintenance period, patients’ mean UPDRS Part III scores improved by 7.0 points (baseline value 29.6 points) in the rotigotine treatment group and by 3.9 points (baseline value 32.0 points) in the placebo treatment group. The mean PDSS-2 total score improved by 5.9 points (rotigotine, baseline value 19.3 points) and 1.9 points (placebo, baseline value 20.5 points), respectively. Treatment differences in the main evaluation metrics were statistically significant (p=0.0002 and p<0.0001).
Skin adhesion
A multicenter, randomized, double-blind, two-way, crossover study compared the skin adhesion of a modified room temperature patch with that of a refrigerated patch. In the study, 52 outpatients received 8 mg/24 h of the rotigotine transdermal patch. The patches were applied 24 hours per day for 2 consecutive days to compare their skin adhesion properties. The study showed that the skin adhesion of the modified room temperature patch was superior to that of the refrigerated patch (full adhesion i.e., >70% of the patch remained adherent to the skin: >90% for the modified room temperature patch; <83% for the refrigerated patch.) . The skin tolerability of the two patches was comparable. Most of the observable skin erythema was mild and no severe erythema appeared.
Domestic clinical trials.
A multicenter, randomized, double-blind, parallel, placebo-controlled study (SP0914) evaluated the efficacy and safety of this product in Chinese patients with early-onset idiopathic Parkinson’s disease. In the study, 124 patients were treated with rotigotine and 123 patients were treated with placebo. Patients received a starting dose of 2 mg/24h, increasing by 2 mg/24h weekly until the optimal dose of rotigotine or placebo, with a maximum dose of 8 mg/24h, followed by 24 weeks of maintenance therapy. At baseline, the mean UPDRS (Part II + III) total score was 32.0 and 32.7 in the rotigotine and placebo groups, respectively. At the end of the maintenance period, the significant improvement in mean UPDRS (Part II + III) total score from baseline values was better in the rotigotine group than in the placebo group (-4.9 and -0.2 points improvement in the rotigotine and placebo groups, respectively; difference in LS means -4.82 points; p<0.0001). a significantly higher proportion of UPDRS (Part II + III) (20%, respectively 25% and 30%) of subjects who responded to treatment, 42.3%, 32.5% and 30.9% in the rotigotine group and 22.3%, 17.4% and 14.0% in the placebo group, respectively; p≤0.0054.
A multicenter, randomized, double-blind, parallel, placebo-controlled study (SP1037) evaluated the efficacy and safety of this product in Chinese patients with advanced idiopathic Parkinson’s disease poorly controlled by levodopa. In the study, 174 patients were treated with rotigotine and 172 patients were treated with placebo. Patients received a starting dose of 4 mg/24h, increasing by 2 mg/24h weekly until the optimal dose of rotigotine or placebo, with a maximum dose of 16 mg/24h, followed by 12 weeks of maintenance therapy. The primary evaluation metric was the absolute change in “off” time from baseline to the end of the double-blind maintenance period. The mean “off” time at baseline was 6.93 hours for the rotigotine group and 6.84 hours for the placebo group in the full analysis set using the Last Observation Carryover (LOCF) method. At the end of the maintenance period, the mean “off” time in the rotigotine group was significantly reduced from the baseline value and was better than that in the placebo group (-2.36 hours and -1.13 hours in the rotigotine and placebo groups, respectively; difference in LS means -1.20 hours; p=0.0002).
[Pharmacology and Toxicology].
Pharmacological effects
Rotigotine is a non-ergotoxic dopamine agonist. The exact mechanism of action of rotigotine in the treatment of Parkinson’s disease is unclear, but it is thought to be related to activation of dopamine receptors in the caudate shell nucleus of the brain.
Toxicological studies
Genotoxicity
Rotigotine has negative results in the Ames test and in vivo bone marrow micronucleus test in mice, and positive results in the tk gene mutation test in mouse lymphoma cells.
Reproductive toxicity
In female rats, no embryos were born in all dose groups after subcutaneous administration of rotigotine (1.5, 5 and 15 mg/kg/day) before mating and during the mating period up to day 7 of gestation, with the lowest dose being twice the maximum recommended human dose (MRHD) of 8 mg/24 h (based on mg/m2). No effect on fertility was seen in male rats administered 70 days before and up to mating, but epididymal sperm viability was reduced at the highest dose, and the non-responsive dose (5 mg/kg/day) was 6 times the MRHD (based on mg/m2). Female rats were injected subcutaneously with rotigotine at doses of 10, 30 and 90 mg/kg/day from 2 weeks before mating to 4 days before mating, and 6 mg/kg/day (approximately 4 times MRHD based on mg/m2) was administered to all test groups from 3 days before mating to day 7 of gestation, and a significant reduction in fertility (low dose) or no fertility at all (medium and high dose) was seen. The effect of rotigotine on rodent implantation is thought to be related to its reduction of prolactin levels. In humans, chorionic gonadotropin, but not prolactin, plays a key role in implantation.
Subcutaneous administration of rotigotine (10, 30, 90 mg/kg/day) to pregnant mice during the organogenesis phase (days 6-15 of gestation) resulted in an increased incidence of delayed skeletal ossification and reduced litter weight at high and medium doses, and increased embryo-fetal mortality at high doses, with a non-responsive dose approximately 6 times higher than MRHD (based on mg/m2). Subcutaneous administration of rotigotine (0.5, 1.5, and 5 mg/kg/day) to pregnant rats during the organogenesis phase (days 6-17 of gestation) resulted in increased embryo-fetal mortality at all doses, with the lowest dose being lower than MRHD (based on mg/m2), and this effect in rats is thought to be related to a decrease in prolactin levels with rotigotine. Subcutaneous administration of rotigotine (5, 10, 30 mg/kg/day) to pregnant rabbits during organogenesis (days 7-19 of gestation) resulted in increased embryo-fetal mortality at high and moderate doses, with a non-responsive dose 12 times higher than MRHD (based on mg/m2).
Subcutaneous administration of rotigotine (0.1, 0.3, 1 mg/kg/day) to rats during gestation and lactation (day 6 of gestation until day 21 postpartum) resulted in impaired growth and long-term neurobehavioral abnormalities during lactation in the offspring of the highest dose group; these offspring mated and also had adverse effects on growth and survival of the next generation; the no-response dose (0.3 mg/kg/day) was lower than MRHD ( based on mg/m2).
Carcinogenicity
Rotigotine was tested for carcinogenicity in mice and rats for 2 years at doses of 3, 10, and 30 mg/kg in mice and 0.3, 1, and 3 mg/kg in rats, all administered by subcutaneous injection every 48 hours. In mice, no increase in tumor incidence was observed at doses up to 9 times the MRHD. In rats, all doses resulted in an increased incidence of testicular mesenchymal cell tumors and uterine tumors (adenocarcinoma, squamous cell carcinoma). The endocrine mechanisms that induce these tumors in rats are not thought to be relevant to humans. Thus, no relevant tumors were seen to be induced at exposures up to 4 to 6 times the plasma exposure (AUC) produced by MRHD.
Other
In a 6-month toxicology trial in albino rats, retinal degeneration was seen in the highest dose [plasma exposure (AUC) of at least 15 times that of MRHD] group of rotigotine. Retinal degeneration was not seen in the 2-year carcinogenicity test in albino rats (albino rats with plasma AUCs up to 4-6 times MRHD) or albino mice, or in the 1-year test in monkeys. The potential significance of this effect in humans has not been determined, but cannot be ignored because it may involve a mechanism of disruption (i.e., retinal detachment) that is prevalent in vertebrates.
[Pharmacokinetics].
1. Pharmacokinetics
(1) Absorption
After administration, rotigotine is continuously released and absorbed through the skin. The patch application 1 to 2 days after reaching steady-state concentration; once a day, the patch is kept on the skin for 24 hours, which can maintain the blood concentration at a stable level. In the dose range of 1mg/24h to 24mg/24h, the blood concentration of rotigotine is proportional to the dose.
Approximately 45% of the active ingredient is released into the skin within 24 hours. The absolute bioavailability after transdermal administration is approximately 37%.
Rotating the application site of the patch can result in daily differences in blood concentrations from day to day. The variation in bioavailability of rotigotine ranged from 2% (upper arm vs. lateral abdomen) to 46% (shoulder vs. thigh). However, no relevant effect on clinical outcomes was shown.
(2) Distribution
The in vitro binding of rotigotine to plasma proteins was approximately 92%. The apparent volume of distribution in humans is approximately 84l/kg.
(3) Metabolism
The metabolism of rotigotine is relatively adequate. Rotigotine is metabolized by N-dealkylation as well as by direct and indirect binding. In vitro studies have shown that different CYP isoforms catalyze the N-dealkylation of rotigotine. The main metabolites are sulfate and glucosinolate conjugates, as well as N-desalkylated metabolites, none of which are biologically active. The metabolite profile is not yet complete.
(4) Elimination
Approximately 71% of the rotigotine dose is excreted in the urine and a small proportion (approximately 23%) is excreted in the feces.
Following transdermal administration, the clearance of rotigotine is approximately 10 l/min, with an overall elimination half-life of 5 to 7 hours. Pharmacokinetic properties show biphasic elimination with an initial half-life of approximately 2 to 3 hours.
The product is administered transdermally and no effects of food or gastrointestinal system conditions are expected.
2. Special patient populations
The starting dose of this product is low and the dose is adjusted gradually according to clinical tolerability to obtain optimal efficacy, so that no dose adjustment according to gender, weight and age is necessary.
Hepatic and renal impairment: No relevant increases in blood levels of rotigotine have been observed in subjects with moderate hepatic impairment or mild to severe renal impairment. No data are available from in-depth studies in patients with severe hepatic impairment.
Blood concentrations of rotigotine conjugates and their dealkylated metabolites increased with increasing renal impairment. However, these metabolites did not produce clinical effects.
3. Pharmacokinetic data in the Chinese population
(1) Healthy Subjects
A trial investigated the pharmacokinetics of 2 mg/24 h single and multiple doses and 4 mg/24 h multiple doses of rotigotine transdermal patch in healthy Chinese subjects. After a short delay (1-4 hours), the blood concentrations of rotigotine gradually increased, reaching steady-state blood concentrations at 16 hours (single dose) and 8 hours (multiple doses), respectively. After removal of the patch, drug absorption ceased and blood concentrations decreased with a half-life comparable to that observed in Caucasians and other races. the percentage of active ingredient absorbed transdermally within 24 hours was comparable to that observed in Caucasians and other races. Steady-state concentrations were achieved after 1-2 days of continuous dosing, and the blood concentrations of rotigotine remained stable during dosing. 2mg/24h and 4mg/24h dosing showed an increase in peak concentration (Cmax), trough concentration (Cmin) and area under the curve (AUC) proportional to the dose at steady state. No drug accumulation was observed with multiple doses. In conclusion, the pharmacokinetic profile of the Chinese population was consistent with that observed in Caucasians and other ethnic groups, with no significant ethnic differences.
(2) Patient population
A trial investigated the pharmacokinetics of rotigotine transdermal patches (administered at doses of 4 mg/24h to 16 mg/24h) in Chinese patients with advanced idiopathic Parkinson’s disease. At the end of the maintenance period, 212 plasma samples were collected for the determination of blood trough concentrations. The blood concentration of rotigotine increased in proportion to the dose and remained stable during the maintenance period. The pharmacokinetic profile of the Chinese patient population was consistent with the results observed in Caucasian and healthy Chinese subjects.
[Storage].
Store below 30°C.
[Package].
Tear-off pouch: one side consists of ethylene copolymer (innermost layer), aluminum foil layer, low-density polyethylene layer and paper layer; the other side consists of polyethylene layer (innermost layer), aluminum foil layer, ethylene copolymer layer and paper layer.
Package specifications.
(1) 2mg/24h: 7 patches/box, 30 patches/box.
(2) 4mg/24h: 7 patches/box, 30 patches/box.
(3) 6mg/24h: 30 patches/box.
(4) 8mg/24h: 30 patches/box.
[Expiry date]
30 months
[Executive Standard]
Imported drug registration standard number: JX20160379
[Approval number]
[Manufacturer]
Company name: UCB Pharma S.A.
Production plant: LTS Lohmann Therapie-Systeme AG
Production Address: Lohmannstr. 2, D-56626 Andernach, Germany
Domestic Contact: Ushibi Trading (Shanghai) Co.
Tel: 021-23210288
Fax: 021-23210399
Free hotline：800 820 6339