Revised according to the latest version of the instructions for the reference preparation of pramipexole hydrochloride tablets (revision date: 29/06/2020)
Date of approval.
Date of revision.
Pramipexole Hydrochloride Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
[Drug Name].
Generic name: Pramipexole Dihydrochloride Tablets
English name: Pramipexole Dihydrochloride Tablets
Hanyu Pinyin：Yansuan Pulakesuo Pian
Ingredients
The main ingredient of this product is pramipexole hydrochloride.
Chemical name: (S)-2-amino-4,5,6,7-tetrahydro-6-(propylamino)-1,3-benzothiazole dihydrochloride monohydrate
Chemical structure formula.
Molecular formula: C10H17N3S-2HCl-H2O
Molecular weight: 302.26
【Properties】.
This product is a white tablet.
Indications】
It is used for the treatment of signs and symptoms of adult idiopathic Parkinson’s disease, i.e., it can be used alone (without levodopa) or in combination with levodopa throughout the course of the disease, including the later stages of the disease, when the efficacy of levodopa gradually decreases or changes and fluctuations (end-of-dose phenomenon or “switch” fluctuations) occur.
It is also used for the treatment of symptoms of moderate to severe idiopathic restless legs syndrome at doses up to 0.75 mg (see [Dosage]).
Specification
According to C10H17N3S-2HCl-H2O (1) 0.25mg (2) 1.0mg
Dosage
All doses are calculated as pramipexole hydrochloride monohydrate.
Parkinson’s disease.
The drug is administered orally, swallowed with water, with or without food intake. The total daily dose is divided equally into three doses a day.
Initial treatment.
Starting dose.
0.375 mg daily is the starting dose, followed by gradual dose increases every 5 to 7 days. If the patient does not experience intolerable adverse reactions, the dose should be increased to achieve maximum efficacy.
Weekly dose (mg) Total daily dose (mg) 13×0.1250.37523×0.250.7533×0.51.50
If further dose increases are required, they should be made on a weekly basis, with each daily dose increasing by 0.75 mg to a maximum daily dose of 4.5 mg. However, it should be noted that the incidence of drowsiness is increased at doses higher than 1.5 mg per day (see [Adverse Reactions]).
Maintenance therapy.
Individual doses should range from 0.375 mg to 4.5 mg per day. In important studies with gradual dose increases, drug efficacy can be observed starting with a daily dose of 1.5 mg. Further dose adjustments should be based on clinical response and incidence of adverse effects. In clinical trials, approximately 5% of patients were taking less than 1.5 mg per day, and in patients with advanced Parkinson’s disease, daily doses greater than 1.5 mg may be effective, at which point care should be taken to reduce the levodopa dose. During the dosing and maintenance phases of this product, it is recommended that the levodopa dosage be reduced according to the individual patient’s response.
Treatment Discontinuation.
Abrupt discontinuation of dopaminergic therapy can lead to the development of nerve blocker malignancy syndrome. Therefore, the drug should be discontinued gradually at a rate of 0.75 mg per day until the daily dose is reduced to 0.75 mg. Thereafter, it should be reduced by 0.375 mg per day.
Dosing in patients with renal impairment.
The clearance of this product is dependent on renal function. For initial treatment it is recommended to apply the following dosing regimen.
Patients with creatinine clearance above 50 ml/min do not need to reduce the daily dose or reduce the number of doses.
For patients with creatinine clearance between 20 and 50 ml/min, the initial daily dose of this product should be divided into two doses, starting with 0.125 mg twice daily (total daily dose of 0.25 mg). The maximum daily dose should not exceed 2.25mg.
In patients with creatinine clearance below 20 ml/min, the daily dose of this product should be taken in one dose, starting with 0.125 mg per day. The maximum daily dose should not exceed 1.5mg.
If renal function decreases during the maintenance phase, reduce the daily dose of this product by the same percentage as the decrease in creatinine clearance, for example, when creatinine clearance decreases by 30%, the daily dose of this product is also reduced by 30%. If creatinine clearance is between 20 and 50 ml/min, the daily dose should be divided into two doses; if creatinine clearance is less than 20 ml/min, the daily dose should be given in one dose.
Dosing in patients with hepatic impairment.
Dose adjustment may not be necessary in patients with hepatic failure, as approximately 90% of the absorbed active ingredient of the drug is excreted through the kidneys. However, the potential effect of hepatic insufficiency on the pharmacokinetics of this product has not been studied.
Restless leg syndrome
The drug is administered orally, swallowed with water, with or without food intake.
The recommended starting dose is 0.125 mg, taken once daily 2 to 3 hours before bedtime. If the patient requires greater symptom relief, the dose may be increased every 4 to 7 days to a maximum daily dose of no more than 0.75 mg (see table below).
Dose escalation steps Once daily evening dose (mg) 10.1252*0.253*0.504*0.75* If treatment is necessary after 3 months the patient’s efficacy should be evaluated and the need for continued treatment reconsidered. If treatment with this product is interrupted for several days, it should be started from the starting dose according to the dosing regimen described above in increasing doses.
Treatment Discontinuation.
Because the daily dose of this product for the treatment of restless legs syndrome does not exceed 0.75 mg, there is no need to taper the dose and treatment with this product can be discontinued directly. In a 26-week placebo-controlled trial, a rebound of restless legs syndrome symptoms (worsening of symptom severity compared to baseline) was observed in 10% of patients (14 of 135) after abrupt discontinuation of treatment. This situation was similar in all dose groups.
Dosing in patients with renal impairment.
Clearance of this product is dependent on renal function and is closely related to creatinine clearance. Patients with creatinine clearance above 20 ml/min do not require a reduction in daily dose. This product has not been studied in patients on hemodialysis or in patients with severe renal impairment.
Dosing in patients with hepatic impairment.
No dose adjustment is required in patients with hepatic failure because approximately 90% of the absorbed active drug ingredient is excreted through the kidneys.
[Adverse Reactions].
Anticipated adverse reactions
The following adverse reactions are expected with the use of this product: abnormal dreaming, amnesia, impulse control disorders and symptoms of compulsive behavior such as overeating, compulsive shopping, hypersexuality and pathological gambling; confusion, constipation, hallucinations, delusions, dizziness, hyperkinesia, cardiac failure, dyskinesia, dyspnea, fatigue, headache, hiccups, cramps, over-eating, hypotension
antidiuretic hormone disorder, insomnia, libido disorder, nausea, paranoia, peripheral edema, pneumonia, pruritus, rash and other allergies; restlessness, drowsiness, sudden sleep onset, syncope, visual impairment including diplopia, blurred vision and decreased vision, vomiting, weight loss including decreased appetite, weight gain.
Based on the results of a combined placebo-controlled trial of a total of 1923 patients taking this product and 1354 patients taking placebo, the incidence of adverse reactions was high in both groups. 63% of patients taking this product and 52% of patients taking placebo reported at least one adverse drug reaction.
Tables 1 and 2 show the incidence of adverse drug reactions in placebo-controlled clinical trials and postmarketing experience in Parkinson’s disease and restless legs syndrome. The adverse drug reactions reported in these tables are those events that occurred at an incidence of 0.1% and greater in patients treated with this product and those that occurred at a higher rate in patients taking this product compared to those taking placebo or were considered clinically relevant. The vast majority of adverse drug reactions are mild to moderate, they usually occur early in treatment, and most tend to resolve when treatment is continued.
The incidence of adverse reactions was classified by system organ using the following categories: very common (≥1 / 10); common (≥1 / 100 to <1 / 10); occasional (≥1 / 1000 to <1 / 100), rare (≥1 / 10,000 to <1 / 1,000); very rare (<1 / 10,000); unclear (cannot be estimated based on available data to estimate).
Parkinson’s disease, the most commonly reported adverse reactions
For the most frequently reported (≥5%) adverse drug reactions, compared with the placebo-treated group, the product treatment group was nausea, dyskinesia, hypotension, dizziness, drowsiness, insomnia, constipation, hallucinations, headache, and fatigue. The incidence of drowsiness increased at doses higher than 1.5 mg daily. Dyskinesia is seen more frequently in combination with levodopa. Hypotension may occur at the start of treatment, especially when the dose is increased too rapidly.
Table 1: Occurrence of adverse reactions in Parkinson’s disease
Systemic organ classification Adverse drug reactions Infection and invasion Occasionally pneumonia Endocrine disorders Occasionally inappropriate secretion of antidiuretic hormone Psychiatric disorders Common dream abnormalities, abnormal behavior (symptoms of impulse control disorder and compulsive behavior), confusion, hallucinations, insomnia Occasionally binge eating, compulsive shopping, delusions, overeating, hypersexuality, dysphoria, paranoia, pathological gambling, mania, delirium rare mania Neurological Disorders very common dizziness, dyskinesia, drowsiness common headache occasional amnesia, spasticity, hyperkinesia, sudden sleep onset, syncope unspecified anterior neck flexion eye disorders common visual impairment including diplopia, blurred vision and decreased vision heart disorders occasional heart failure vascular disorders common hypotension respiratory, thoracic and mediastinal disorders occasional dyspnea, hiccups gastrointestinal disorders very common nausea common constipation Skin and subcutaneous tissue disorders occasionally allergy, pruritus, rash systemic symptoms and site conditions common fatigue, peripheral edema unspecified drug withdrawal syndrome (dopamine agonist withdrawal syndrome) (see [Precautions]) other common weight loss including decreased appetite occasionally weight gain
Restless legs syndrome, the most common adverse reaction
The most commonly reported (≥5%) adverse drug reactions in patients with restless legs syndrome treated with this product were nausea, headache, dizziness, and fatigue. Nausea and fatigue were more common in female patients treated with this product (20.8% and 10.5%, respectively) compared to males (6.7% and 7.3%, respectively).
Table 2: Occurrence of adverse reactions in restless legs syndrome
Systemic organ classification Adverse drug reactions Infection and invasion Unclear pneumonia Endocrine disorders Occasionally inappropriate secretion of antidiuretic hormone Psychiatric disorders Common dream abnormalities, insomnia Occasionally abnormal behavior (symptoms of impulse control disorder and compulsive behavior) such as binge eating, compulsive shopping, hypersexuality and pathological gambling, confusion of consciousness, delusions, hallucinations, overeating, sexual desire disorder, paranoia, agitation, mania, delirium Neurological Disorders common dizziness, headache, drowsiness occasional amnesia, dyskinesia, hyperkinesia, spasticity, sudden sleep onset, syncope unspecified anterior neck flexion eye disorders occasional visual impairment including diplopia, blurred vision and decreased vision heart disorders occasional heart failure vascular disorders occasional hypotension respiratory, thoracic and mediastinal disorders occasional dyspnea, hiccups gastrointestinal disorders very common nausea common constipation, vomiting Skin and subcutaneous tissue disorders occasional allergy, pruritus, rash systemic symptoms and site conditions common fatigue occasional peripheral edema unspecified drug withdrawal syndrome (dopamine agonist withdrawal syndrome) (see [Precautions]) other occasional weight loss including decreased appetite, weight gain
Drowsiness
Common drowsiness, occasionally excessive daytime sleepiness and sudden sleep onset
Sexual desire disorder
Occasional libido disorders (increase or decrease)
Impulse control disorders and compulsive behavior
Patients with Parkinson’s disease treated with dopamine receptor agonists, including this product, especially at high doses, have been reported to exhibit signs of pathological gambling, increased libido, and hypersexuality, usually reversible when the dose is reduced or discontinued.
In a cross-sectional, retrospective screening and case-control study including 3090 patients with Parkinson’s disease, 13.6% of all patients treated with dopamine or non-dopaminergic medications in the past 6 months had symptoms of impulse control disorders. Clinical manifestations observed included pathological gambling, compulsive shopping, binge drinking and compulsive sexual behavior (hypersexuality). Possible independent risk factors for impulse control disorders include: dopaminergic medication and higher doses of dopaminergic medication, younger age (≤65 years), unmarriedness and family history of self-reported gambling behavior.
Heart Failure
Heart failure has been reported in clinical studies and post-marketing follow-up of pramipexole. A pharmacoepidemiological study showed that
increased risk of heart failure with pramipexole compared to no pramipexole use. However, a causal relationship between the use of pramipexole and heart failure has not been confirmed.
Contraindications]
Hypersensitivity to the active ingredient or any of the excipients of this product.
Precautions】
Sleeping during daily activities
Sleeping during daily activities, including driving a motor vehicle, has been reported in patients treated with this product and has sometimes led to accidents. Although most of these patients report drowsiness while taking this product, some believe that they do not present with premonitory signs such as excessive drowsiness and believe they were alert prior to the event. Some of these events were reported one year after initiation of treatment.
Somnolence is a frequent event in patients receiving more than 1.5 mg/day (0.5 mg/dose three times daily) of this product for Parkinson’s disease. In controlled clinical trials for the treatment of restless legs syndrome, the incidence of somnolence was 6% in patients receiving this product at 0.25 to 0.75 mg once daily, compared to 3% in placebo-treated patients. Many clinical experts believe that falling asleep while engaged in daily activities always occurs in the context of a preexisting narcolepsy, although patients may not give such a history. Prescribers should therefore continually reassess the patient’s sleepiness or drowsiness, especially if events have occurred since the start of treatment. Prescribers should also be aware that the patient may not acknowledge sleepiness or drowsiness until asked directly about it during a specific event.
Prior to initiation of therapy with this product, patients should be informed of the possibility of drowsiness and specifically asked about factors that may increase the risk of this product, such as concomitant sedative medications, the presence of sleep disturbances and concomitant medications that increase plasma levels of this product (e.g., cimetidine ~ see Drug Interactions). If a patient experiences significant daytime sleepiness or falls asleep during activities that require active participation (e.g., talking, eating, etc.), the drug should usually be discontinued. If the decision is made to continue, patients should be advised not to drive and to avoid other potentially hazardous activities. Although dose reduction may significantly reduce the degree of drowsiness, there is insufficient information to confirm that dose reduction will eliminate the occurrence of drowsiness during daily activities.
Orthostatic hypotension
In clinical studies and clinical experience, dopamine receptor agonists appear to impair the systemic regulation of blood pressure, thus causing upright hypotension, especially during dose increases. In addition, patients with Parkinson’s disease appear to have impaired ability to respond to upright stimuli. For these reasons, patients with Parkinson’s disease and restless legs syndrome who are being treated with dopamine agonists usually need to be monitored closely for symptoms of upright hypotension, especially during dose increases, and should be informed of this risk (see Cautionary Information for Patients in [Precautions]).
In clinical trials of this product, the incidence of clinically significant upright hypotension reported by patients receiving this product was not higher than that reported by patients receiving placebo, despite the apparent effect of body position in normal volunteers. This result, particularly for the higher doses used to treat Parkinson’s disease, was clearly unexpected based on previous experience with the risks of dopamine agonist therapy.
Although this result may reflect properties specific to this product, it can also be explained by the different study conditions and the nature of the population enrolled in the clinical trial. Patients were cautiously dose increased and those with active cardiovascular disease or significant upright hypotension were excluded. Also, clinical trials in patients with restless legs syndrome did not include upright stimulation trials with close blood pressure monitoring close to the time of dosing.
Hallucinations
In 3 double-blind, placebo-controlled trials in early Parkinson’s disease, hallucinations were observed in 9% (35 of 388 patients) of patients taking this product compared to 2.6% (6 of 235) of patients receiving placebo. In four double-blind, placebo-controlled trials in advanced Parkinson’s disease in which patients took this product and the concomitant drug levodopa, hallucinations were observed in 16.5% (43 of 260 patients) of patients receiving this product compared with 3.8% (10 of 264) of patients receiving placebo. 3.1% of patients with early Parkinson’s and 2.7% of patients with advanced Parkinson’s had hallucinations that were severity led to discontinuation of medication.
In contrast, only 0.4% of patients taking placebo in both the early and late Parkinson’s disease groups discontinued their medication due to hallucinations.
Age appears to increase the risk of hallucinations due to this product. In patients with early Parkinson’s disease, the risk of hallucinations was 1.9 times greater than in the placebo group for patients younger than 65 years of age, and 6.8 times greater than placebo for patients older than 65 years of age. In patients with advanced Parkinson’s disease, the risk of hallucinations was 3.5 times greater than in the placebo group for patients younger than 65 years of age and 5.2 times greater than placebo for patients older than 65 years of age.
In restless legs syndrome Clinical study, one case of hallucinations occurred in a patient treated with this product (out of 889 patients); symptoms disappeared after discontinuation of treatment.
Transverse rhabdomyolysis
A rare case of rhabdomyolysis occurred in a 49-year-old male with advanced Parkinson’s disease treated with this product. The patient was hospitalized with elevated phosphocreatine kinase (CPK) (10631 IU/L). These symptoms subsided after discontinuation of the drug.
Renal Impairment
Because this product is eliminated by the kidneys, it should be taken with caution in patients with renal insufficiency (see [DOSAGE AND ADMINISTRATION]).
Movement disorders
This product may potentiate the dopaminergic adverse effects of levodopa and may cause or exacerbate pre-existing dyskinesia. Reducing the levodopa dose may improve this adverse effect.
Retinal Pathology in Rats
In a 2-year carcinogenicity study, lesions (degeneration and loss of photoreceptor cells) were observed in the retinas of rats. Although retinal degeneration was not diagnosed in colored rats treated for 2 years, the outer nuclear layer of the retina was thinner in rats given the drug compared to controls. There were no similar findings in retinal assessments in mice, monkeys, and miniature pigs. The potential significance of the results for humans is uncertain, but cannot be ignored, as this structural disruption of the organism (i.e., optic disc degeneration), which is widespread in vertebrates, may also occur in humans.
Reported events related to dopaminergic drug therapy
Although the events listed below may not have been reported in connection with the use of this product in the study program, they have been associated with the use of other dopaminergic drugs. However, the expected incidence of these events is low, and even if this product were to experience these adverse events at a rate similar to that of other dopaminergic drugs, there have not been enough cases of any of these adverse events in the studies to date with the exposed population of this product.
Acute hyperthermia and confusion after withdrawal
Although not reported in clinical research programs in association with this product, it is a syndrome similar to the malignant syndrome of nerve blockers (characterized by elevated body temperature, muscle rigidity, altered state of consciousness, and autonomic dysfunction) with no other apparent etiology, and is thought to be associated with rapid dose reduction, withdrawal, or changes in antiparkinsonian therapy.
Complications of fibrosis
Although not reported in clinical research programs in association with this product, retroperitoneal fibrosis, pulmonary infiltrates, pleural effusions and pleural thickening, pericarditis, and heart valve disease have been reported in some patients treated with ergot-derived dopaminergic drugs. Although these complications may subside when the drug is discontinued, complete subside does not always occur.
While these adverse events are thought to be related to the ergot-like structure of these compounds, it is unclear whether other non-ergot-derived dopamine receptor agonists contribute to these adverse events.
A few reports of possible fibrotic complications, including peritoneal fibrosis, pleural fibrosis, and pulmonary fibrosis, have been received after the introduction of this product. Although the evidence is insufficient to establish a causal relationship between this product and these fibrotic complications, in these rare cases, the effects of this product cannot be completely excluded.
Drug Withdrawal Syndrome
Drug withdrawal syndromes have been reported during or after discontinuation of dopamine agonists, including pramipexole. Risk factors may include high cumulative dopaminergic exposure. Withdrawal symptoms are not responsive to levodopa and may include apathy, anxiety, depression, fatigue, sweating, and pain. Patients should be informed of possible withdrawal symptoms prior to discontinuation and monitored closely during and after discontinuation. If severe discontinuation symptoms occur, consider temporarily giving the lowest effective dose of dopamine agonist again.
Melanoma
Epidemiological studies have shown that patients with Parkinson’s disease have a higher risk of developing melanoma than the general population (approximately 2-6 times higher). Whether this increased risk of developing melanoma is due to Parkinson’s disease or other factors (such as the medications used to treat Parkinson’s disease) is not known.
Therefore, when using this product to treat any disease, it is recommended that patients and providers should be monitored frequently and regularly for the development of melanoma. Ideally, periodic skin examinations should be performed by a specialist (e.g., a dermatologist).
Dystonia
Patients with Parkinson’s disease may present with axial dystonia such as anterior cervical flexion, anterior trunk flexion disorder or lateral arch reversion (Pisa syndrome). Dystonia has occasionally been reported following the use of dopamine agonists, including pramipexole, although a causal relationship between the drugs has not been established. Dystonia may also occur several months after the initiation of medication or dose adjustment. If dystonia occurs, the dopaminergic medication regimen should be reviewed and adjustments considered.
Patients with schizophrenia
Patients with schizophrenia should be treated with dopamine agonists only if the potential benefits outweigh the risks. Concomitant administration of antipsychotics and pramipexole is not recommended and dopamine antagonistic effects can be expected.
Discontinuation of treatment for Parkinson’s disease
Abrupt discontinuation of dopaminergic therapy has been reported to suggest symptoms of nerve blocking malignant syndrome.
Rebound and exacerbation of restless legs syndrome
Reports in the literature suggest that dopaminergic treatment of restless legs syndrome (RLS) can lead to a shift in symptoms to the early morning hours, called rebound. Rebound was not reported in clinical trials of this product, but the duration of the trials was generally not long enough to detect this phenomenon, and exacerbations were also observed during RLS treatment. Exacerbations are defined as the onset of symptoms earlier in the evening (or even in the afternoon), an increase in symptoms, and the spread of symptoms to other extremities. In a controlled trial of this product for RLS, at the end of a 3-month course of treatment
Both this product and placebo-treated patients had approximately 20% reporting symptoms at least two hours earlier in the day. The incidence and severity of exacerbation and/or rebound of RLS following long-term use of this product and the proper management of these events have not been adequately evaluated in controlled clinical trials.
Information for Patient Use Precautions
Patients should be advised to take this product only as prescribed.
Patients should be aware of the potential sedative effects associated with this product, including drowsiness and the possibility of falling asleep while performing daily activities. Drowsiness is a common adverse event with potentially serious consequences, and patients should not drive or engage in other potentially hazardous activities until they have gained sufficient experience with the use of this product to understand whether it may adversely affect their mental and/or motor abilities. It is recommended that patients should not drive or engage in potentially hazardous activities if they experience increased drowsiness or episodes of falling asleep during daily life (e.g., watching television, riding in a car, etc.) at any time during treatment and should consult a physician for advice. Due to possible additive effects, caution is advised when patients are taking other sedative medications or drinking alcohol and taking concomitant medications (e.g., cimetidine) that can increase plasma levels of this product in combination.
Patients should be advised that hallucinations may occur and that older patients with Parkinson’s disease are at higher risk than younger patients with Parkinson’s disease. In clinical trials, hallucinations were rare in patients treated with this product for restless legs syndrome.
Strong desire to gamble, increased sexual desire, and other strong desires that cannot be controlled have been reported in patients when taking one or more drugs that increase the function of central dopamine neurons (usually used to treat Parkinson’s disease), including this product. Although not proven to be caused by these drugs, it has been reported that in some cases these desires stop when the dose is reduced or stopped. Therefore, when patients are receiving this drug, prescribers should ask patients if new or enhanced gambling desires, sexual desires, or other cravings are occurring. Patients should inform their physician if new or enhanced gambling cravings, increased sexual desire, or other strong cravings occur while they are taking this product. If these strong cravings occur while the patient is taking this product, the physician should consider lowering the dose or discontinuing the drug.
Patients may experience upright hypotension, which may be accompanied by dizziness, nausea, fainting or dark haze, and sometimes sweating or asymptomatic. Hypotension may occur more frequently during initial treatment. Therefore, patients should be cautioned not to stand quickly after sitting or lying down, especially if they have been in this state and at the start of treatment with this product.
Because the teratogenic potential of pramipexole has not been fully established in test animals and because of limited experience with human use, patients should inform their physician if they become pregnant or plan to become pregnant during treatment.
Because pramipexole may be secreted via breast milk, patients should inform their physician if they plan to breastfeed or are breastfeeding an infant.
If patients experience nausea, it is recommended that taking this product with a meal may reduce the incidence of nausea.
Laboratory Tests
During the development of this product, routine laboratory tests did not reveal systemic abnormalities. Therefore, specific guidelines cannot be provided to guide routine monitoring; it is the responsibility of the practitioner to determine how best to monitor the patient at the time of care.
Effects on the ability to drive and operate machinery
Patients should be advised that hallucinations may occur and may impair the ability to drive.
Patients should be aware of potential sedative effects associated with the use of this product, including drowsiness and sudden sleep episodes during daily life (see [Precautions]). Because drowsiness is a common adverse event and has the potential to cause serious consequences, patients should avoid driving vehicles or operating machinery until they have had sufficient experience with the drug to determine whether it affects their mental status and/or motor ability. Patients should not drive vehicles or participate in potentially hazardous activities if drowsiness or the frequency of sudden sleepiness increases during treatment, and should consult a physician for advice.
For Pregnant and Lactating Women
The effects of this product on human pregnancy and lactation have not been studied. It is not teratogenic to rats and rabbits, but is embryotoxic to rats at maternal toxic doses. This product is contraindicated during pregnancy unless truly necessary and only when the potential benefit outweighs the potential risk to the fetus.
It has a lactation-inhibiting effect due to the inhibition of prolactin secretion in humans by treatment with this product. The secretion of this product into female breast milk has not been studied. The concentrations of radioactivity associated with the active substance in rat milk were higher than those in plasma.
Due to the lack of human data, this product should not be used during lactation. However, if use of this product is unavoidable, lactation should be discontinued.
The effects of this product on human reproduction have not been studied. As expected, as a dopamine agonist, it has been shown to affect the estrous cycle and reduce fertility in females in animal studies. However, these studies did not show a direct or indirect impairment of fertility in males.
Pediatric Use
Due to the lack of safety and efficacy data, the use of this product in children and adolescents under 18 years of age is not recommended.
Geriatric use]
Subjects older than 65 years of age have an approximately 30% lower total clearance of this product when administered orally compared to younger subjects, as their decreased renal clearance is due to age-related decreases in renal function. This resulted in an increase in the elimination half-life from approximately 8.5 hours to 12 hours. In clinical studies of patients with Parkinson’s disease, 38.7% of patients were older than 65 years of age. There were no significant differences in efficacy or safety between older and younger patients, except for an increased relative risk of hallucinations associated with the use of this product in older patients. In the clinical study of patients with restless legs syndrome, 22% of patients were at least 65 years old. There were no significant differences in efficacy or safety between older and younger patients.
[Drug Interactions].
Plasma Protein Binding
The product binds to plasma proteins to a very low degree (<20%) and shows little biotransformation in men. Therefore, it is unlikely to interact with other drugs that affect plasma protein binding or to be cleared by biotransformation. Although interaction with anticholinergics has not been studied, the potential for interaction is limited because anticholinergics are primarily cleared by biotransformation. There are no pharmacokinetic interactions with slegiline and levodopa
.
Inhibitors/competitors of the renal clearance pathway of active ingredients
Cimetidine reduces the renal clearance of this product by approximately 34%, probably by inhibiting the renal tubular cation secretory transport system. Therefore, inhibitors of the renal clearance pathway of the active ingredient, or drugs cleared by this pathway, such as cimetidine, amantadine, and mexiletine, zidovudine, cisplatin, quinine, and procainamide may interact with this product, resulting in a decrease in clearance of this product. When these drugs are co-administered with this product, a lower dose of this product should be considered.
Co-levodopa
When this product is co-administered with levodopa, a decrease in the levodopa dose is recommended when increasing the dose of this product, while the dose of other antiparkinsonian drugs remains unchanged.
Due to possible additive effects, patients should use caution when taking this product in conjunction with other sedative drugs or alcohol.
Antipsychotics
Combination with antipsychotics should be avoided, e.g., if antagonistic effects can be anticipated.
[Drug overdose].
Symptoms
There is no clinical experience with massive drug overdose. Anticipated adverse events may be those related to the pharmacodynamic profile of dopamine agonists, including nausea, vomiting, seizures, hallucinations, agitation, and hypotension.
Treatment
There is no clear antidote for dopamine agonist overdose. If symptoms of central nervous system excitation are present, treatment with neuroleptic drugs may be required. Overdose may require general supportive management measures, as well as gastric lavage, intravenous fluids, administration of activated charcoal, and cardiac monitoring.
Hemodialysis has been shown to be of no help in detoxification.
Pharmacology and Toxicology]
Pharmacodynamic properties
It is a dopamine receptor agonist with high selectivity and specificity for binding to the D2 subfamily of dopamine receptors, with preferential affinity for the D3 receptors therein; and has full intrinsic activity.
It reduces dyskinesia in Parkinson’s disease through excitation of dopamine receptors in the striatum. Animal tests have shown that it inhibits the synthesis, release and renewal of dopamine. It protects dopamine neurons from degeneration due to ischemia or methamphetamine neurotoxicity.
The exact mechanism of action of this product in the treatment of restless legs syndrome is not known. Although the pathophysiological mechanism of restless legs syndrome is largely unknown, neuropharmacological evidence suggests that it may be primarily related to the dopaminergic system. Positron emission tomography (PET) studies suggest that mild striatal presynaptic dopaminergic abnormalities may be associated with the pathogenesis of restless legs syndrome.
In vitro studies have demonstrated the ability of this product to protect neurons from levodopa-induced neurotoxicity.
A dose-dependent decrease in prolactin was observed in volunteers.
Preclinical Safety Data
Repeated dose toxicity studies showed functional effects, primarily involving the central nervous system in rats and the reproductive system in female rats, possibly due to amplified pharmacodynamic effects of this product.
Decreases in diastolic blood pressure, systolic blood pressure and heart rate were observed in tests in small pigs, and a tendency toward hypotensive effects was observed in tests in monkeys.
Experimental studies in rats and rabbits revealed a potential effect on reproductive function. It is not teratogenic in rats and rabbits, but has toxic effects on rat embryos at maternally toxic doses. The effects of prolactin on pregnancy and female rat fecundity have not been fully elucidated due to the lowering of prolactin secretion and the specific effects of prolactin on female rat reproductive function.
The product is not genotoxic. In a carcinogenicity test, male rats developed testicular mesenchymal cell hyperplasia and adenoma, which could be explained by the prolactin-inhibiting effect of this product. However, the finding was not clinically relevant to male humans. The same trial also showed an association with retinal degeneration in rats at doses of 2 mg/kg and higher, but there were no similar findings in colored rats, 2-year-old mice in carcinogenicity tests, or other studied populations.
Pharmacokinetics]
This product is rapidly and completely absorbed orally. The absolute bioavailability is higher than 90%, and the maximum plasma concentration occurs between 1 and 3 hours after dosing. The absorption of this product is not reduced when taken with food, but the rate of absorption is reduced.
The product shows linear kinetics with minimal inter-patient variation in plasma levels.
In humans, the plasma protein binding of this product is very low (less than 20%) and the volume of distribution is large (400 L). High concentrations of the drug in rat brain tissue (approximately 8 times the plasma concentration) were observed.
The product is metabolized to a very low degree in males.
The drug is excreted from the kidneys primarily in its native form, accounting for approximately 80% of the administered dose. approximately 90% of the 14C-labeled drug is excreted through the kidneys, with less than 2% of the drug in the feces. The total clearance of this product is approximately 500 ml/min and the renal clearance is approximately 400 ml/min. The elimination half-life (t1/2) varies from 8 to 12 hours in young and elderly people.
Storage
Seal and store under 30℃ away from light.
Package】
PVC solid pharmaceutical hard tablets and pharmaceutical aluminum foil packaging.
(1) 0.25mg specification: 6 tablets/plate×3 plates/box, 10 tablets/plate×3 plates/box.
(2) 1.0mg specification: 6 tablets/plate x 3 plates/box, 10 tablets/plate x 3 plates/box.
Expiration date
12 months
Execution standard
Approval number】
(1) 0.25mg specification: State Drug Registration H20183367
(2) 1.0mg specification: State Drug Quantifier H20183368
Marketing license holder
Name: Zhejiang Jingxin Pharmaceutical Co.
Registered address: No. 800 East Xinchang Avenue, Yulin Street, Xinchang County, Zhejiang Province
Manufacturer
Company Name: Zhejiang Jingxin Pharmaceutical Co.
Address: No. 800, East Xinchang Avenue, Yulin Street, Xinchang County, Zhejiang Province
Postal Code: 312500
Sales Hotline: (0575) 86096832
Complaint phone: (0575) 86098209
Fax number: (0575) 86096898
Web Address: www.jingxinpharm.com