Date of approval.
Date of revision.
Pramipexole Hydrochloride Extended Release Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic name: Pramipexole Dihydrochloride Sustained-release Tablets
English name: Pramipexole Dihydrochloride Sustained-release Tablets
Hanyu Pinyin: Yansuan Pulakesuo Huanshipian
Ingredients
The main ingredient of this product: Pramipexole hydrochloride
Chemical name: (S)-2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole-dihydrochloride monohydrate
Chemical structure formula.
Molecular formula: C10H17N3S-2HCl-H2O
Molecular weight: 302.26
Properties
This product is white tablet or off-white tablet.
Indications】
This product is used to treat the 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 late stage of the disease, when the efficacy of levodopa gradually decreases or when there are changes and fluctuations (end-of-dose phenomenon or “switch” fluctuations).
Specification
According to C10H17N3S-2HCl-H2O (1) 0.375mg (2) 1.5mg
Dosage
All doses are calculated as Pramipexole Hydrochloride Monohydrate.
Take the drug orally, once a day.
Initial treatment.
Starting dose.
0.375 mg daily is the starting dose, then gradually increase the dose every 5 to 7 days. If the patient does not experience intolerable adverse reactions, the dose should be increased to achieve maximum efficacy.
Total daily dose (mg) Week 1 0.375 Week 2 0.75 Week 3 1.50 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. It should be noted that the incidence of drowsiness is increased at doses higher than 1.5 mg per day (see [Adverse Reactions]).
Patients already taking pramipexole hydrochloride tablets may be switched to this product overnight with their current daily therapeutic dose in equal doses. After conversion to this product, the dose should be adjusted based on the patient’s therapeutic response. (See [Clinical Trials]).
Maintenance therapy.
Individual doses should range from 0.375 mg to 4.5 mg per day. In pivotal studies with gradual dose increases, drug efficacy can be observed starting with a daily dose of 1.5 mg. Further dose adjustments should be made 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 levodopa dosage be reduced based on the individual patient’s response.
Missed Doses.
When a dose is missed, the product should be taken no later than 12 hours after the regular dosing time. If more than 12 hours have elapsed, the missed dose may be ignored and the next dose should be taken at the next day’s regular dosing time.
Treatment Discontinuation.
Abrupt discontinuation of dopaminergic therapy can lead to the development of neuroblocker malignancy syndrome. Therefore, it 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 30 and 50 ml/min, the initial daily dose of this product should be 0.375 mg every other day. After one week of administration of this product, the therapeutic response and tolerability of this product should be carefully evaluated before increasing the daily dose. If further dose increases are required, increase the dose by 0.375 mg on a weekly cycle, with the maximum daily dose not exceeding 2.25 mg.
Treatment with this product is not recommended for patients with creatinine clearance below 30 ml/min and there are no supporting data for this patient population. In this case, consider taking Pramipexole Hydrochloride tablets.
If renal function decreases during the maintenance phase of therapy, follow the above recommendations.
Dosing in patients with hepatic impairment.
Dose adjustment may not be necessary in patients with hepatic failure, as approximately 90% of the absorbed active drug ingredient is excreted through the kidneys. However, the potential effect of hepatic insufficiency on the pharmacokinetics of this product has not been studied.
Method of administration.
This product is swallowed with water and should not be chewed, broken or crushed. This product may or may not be taken with or without food. This product should be taken at the same time each day.
Adverse reactions]
Expected adverse reactions
The following adverse reactions are expected with the use of this product: dream abnormalities, amnesia, impulse control disorders and symptoms of compulsive behavior (such as binge eating, compulsive shopping, hypersexuality and pathological gambling), heart failure, confusion, constipation, hallucinations, delusions, dizziness, hyperkinesia, dyskinesia, dyspnea, fatigue, headache, hiccups, cramps, overeating, hypotension, antidiuretic hormone secretion disorders, insomnia, libido disorders, 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.
In the placebo-controlled clinical trial, a total of 1778 patients took the product and 1297 patients took placebo. The combined analysis showed a high incidence of adverse reactions in both groups, with 67% of patients taking this product and 54% of patients taking placebo reporting at least one adverse drug reaction.
The following table shows the incidence of adverse drug reactions in placebo-controlled clinical trials. Adverse drug reactions reported in the table are events with an incidence of 0.1% or greater and events that occurred at a higher rate in patients taking this product compared to the placebo group, or events that were considered clinically relevant. The vast majority of adverse reactions are mild to moderate, usually occurring early in treatment, and most tend to resolve with continued treatment.
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).
For the most frequently reported (≥ 5%) adverse drug reactions, compared to the placebo-treated group, were 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 beginning of treatment, especially when the dose of this product is increased too rapidly.
Systemic organ classification Adverse drug reactions Infection and invasion Occasionally pneumonia Endocrine disorders Occasionally disorders of antidiuretic hormone secretion Psychiatric disorders Common dream abnormalities, abnormal behavior (symptoms of impulse control disorder and compulsive behavior), confusion of consciousness, hallucinations, insomnia Occasionally binge eating1, compulsive shopping, delusions, overeating1, 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 forward neck flexion eye disorders common visual impairment including diplopia, blurred vision, and decreased vision heart disorders occasional heart failure1 vascular disorders common 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 administration site conditions common fatigue, peripheral edema unclear dopamine agonist withdrawal syndrome, including apathy, anxiety, depression, fatigue, sweating, and pain Other common weight loss includes decreased appetite occasional weight gain1 The adverse reaction was observed in postmarketing information for the product. There is a 95% certainty that the frequency level of this adverse reaction is no more than incidental and may even be lower. Since this adverse reaction was not observed in the clinical trial database of 2762 patients with Parkinson’s disease, it is unlikely that a precise frequency of occurrence can be assessed.
Drowsiness
Drowsiness is common, with occasional excessive daytime sleepiness and sudden episodes of sleep.
Sexual desire disorder
Sexual desire disorders (increased or decreased) are occasionally seen.
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 a family history of self-reported gambling behavior. Heart Failure Based on clinical trials and post-marketing information on the product, patients using pramipexole have reported adverse effects of heart failure. A pharmacoepidemiological study found that pramipexole use was associated with an increased risk of heart failure compared with no pramipexole use (observed hazard ratio 1.86; 95% CI, 1.21 to 2.85). A causal relationship between pramipexole and heart failure has not been confirmed.
[Contraindication].
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 drug, sometimes resulting in 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. In the Parkinson’s placebo-controlled trial, sudden onset of sleep or drowsiness was observed in 2% (8 of 387 patients) of patients taking the product compared to 1% (2 of 281) of patients receiving placebo.
In patients with early Parkinson’s disease, drowsiness was observed in 36% (223) of patients taking moderate doses of this product (3.0 mg/day) compared to 15% (103) of patients receiving placebo. In patients with advanced Parkinson’s disease, drowsiness was observed in 15% (164) of patients taking moderate doses (3.0 mg/day) compared to 16% (178) of patients receiving placebo. Many clinical experts believe that falling asleep while engaged in daily activities always occurs in the context of a preexisting somnolence, 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.
Symptomatic upright 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 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 information on patient use precautions in [Precautions]). In placebo-controlled trials, symptomatic upright hypotension was observed in 3% (10 of 387) of patients taking this product compared with 1% (3 of 281) of patients receiving placebo. 1 of 387 patients taking this product discontinued treatment due to hypotension.
Because of the risk of causing postural hypotension, the drug should be used with caution in patients with severe cardiovascular disease. Blood pressure monitoring is recommended, especially at the start of treatment.
Impulse control disorder/compulsive behavior
Results in case reports and cross-sectional studies have shown that when one or more drugs, including this product, are taken to increase dopaminergic effects and are widely used to treat Parkinson’s disease, pathological gambling, increased sexual desire, compulsive shopping, binge eating and other compulsive behaviors occur, and patients are unable to control these compulsive behaviors. In some cases, although not all, the compulsive behaviors disappear when the dose is reduced or the drug is discontinued. Since patients do not admit to abnormal behavior, it is important that prescribers clearly ask patients or their caregivers about new or enhanced pathological gambling, increased libido, compulsive shopping and other compulsive behaviors when taking this drug. When these compulsive behaviors occur in patients taking this product, prescribers should consider reducing the dose or discontinuing the drug. (See information on patient use precautions in [Precautions])
A total of 1056 patients with Parkinson’s disease participated in two groups (this product versus placebo controls) in a study lasting 33 weeks, and each time patients were asked about the incidence of these symptoms. Compulsive behaviors, including pathological gambling, increased sexual desire, and with/without compulsive shopping, were observed in 14 of 387 patients (4%) in the treatment trial with this product, 12 of 388 (3%) in the treatment trial with pramipexole hydrochloride, and 4 of 281 (1%) in the placebo-controlled trial.
Hallucinations and psychotic-like behavior
In placebo-controlled trials in Parkinson’s disease, hallucinations (visual or auditory or mixed hallucinations) were observed in 6% (25 of 387 patients) of patients taking this product compared to 2% (5 of 281) of patients receiving placebo. 1% (5 of 387) of patients taking this product discontinued due to hallucinations.
Age appeared to increase the risk of hallucinations due to this product. In placebo-controlled trials, hallucinations were observed in 9% (15 of 162) of patients older than or equal to 65 years of age taking this drug compared to 4% (10 of 225) of patients younger than 65 years of age.
Post-marketing reports of dopamine agonists, including this product, suggest that patients may experience new or worsening changes in mental status and behavior, which may be severe, including psychotic-like behavior, during or after initiation of treatment with this product or an increase in its dose. Other medications used to improve symptoms of Parkinson’s disease may have similar effects on thinking and behavior. Such abnormal thinking and behavior may include one or more of a variety of manifestations, including paranoid thoughts, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium.
Patients with severe psychiatric disorders should not usually be treated with dopamine agonists (including this product) because of the risk of exacerbating psychosis. In addition, certain drugs used to treat psychosis may exacerbate symptoms of Parkinson’s disease and may reduce the efficacy of this product. Patients with psychosis should be treated with dopamine agonists only if the potential benefits outweigh the risks, and the combination of antipsychotics with pramipexole should be avoided.
Movement disorders
This product may potentiate dopaminergic adverse reactions to levodopa and may cause or exacerbate pre-existing dyskinesias.
Dyskinesia
Axial dystonia, including anterior cervical flexion, anterior trunk flexion disorder (spinal curvature syndrome), and lateral arch reversion (Pisa syndrome), has been reported occasionally after initiation of pramipexole administration or elevated doses in patients with Parkinson’s disease. Although dystonia may be a symptom of Parkinson’s disease, symptoms have improved in these patients following dose reduction or discontinuation of pramipexole. Dose adjustment of pramipexole should be considered if dystonia is present.
Renal Impairment
This product is eliminated by the kidneys. No daily dose reduction is required in patients with mild renal impairment (creatinine clearance above 50 ml/min). This product has not been studied in patients with moderate or severe renal impairment (creatinine clearance less than 50 ml/min), or in patients on hemodialysis. (See [Dosage and Administration])
Rhabdomyolysis
A rare case of rhabdomyolysis occurred in a 49-year-old male with advanced Parkinson’s disease treated with this product in a clinical study of pramipexole hydrochloride tablets. The patient was hospitalized with elevated phosphocreatine kinase (CPK) (10631 IU/L). These symptoms subsided after discontinuation of the drug.
Patients are advised to consult their physician if unexplained muscle pain, pressure, or weakness that resembles rhabdomyolysis symptoms occur.
Retinal Pathology
Human data
A two-year, open, randomized, parallel-group, safety study evaluating retinal deterioration and visual acuity compared pramipexole immediate-release tablets with ropinirole immediate-release tablets. Two hundred and thirty-four patients with Parkinson’s disease (115 receiving pramipexole at a mean dose of 3.0 mg/day and 119 receiving ropinirole at a mean dose of 9.5 mg/day) were evaluated using a battery of clinical ophthalmologic assessments. Of the 234 evaluable patients, 196 received treatment for two years and 29 were judged to have clinical abnormalities considered meaningful (19 patients in each treatment group received treatment for less than two years). There was no statistical difference in retinal deterioration between treatment groups; however, the study was only able to detect very large differences between treatment groups. In addition, because the study did not include an untreated comparison group (placebo-treated), it is not clear whether the outcomes reported among patients treated with either drug are greater than the background incidence in the elderly population.
Ophthalmic monitoring is recommended for patients treated with pramipexole either regularly or when visual abnormalities occur.
Data from animal studies
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 thinned more 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 this result for humans is uncertain, but it 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.
Dopamine agonist withdrawal syndrome
The decision to discontinue pramipexole therapy in patients with Parkinson’s disease should be made by gradually decreasing the dose (see [DOSAGE]). Non-motor adverse effects may occur when dopamine agonist (including pramipexole) therapy is tapered or discontinued. Symptoms may include apathy, anxiety, depression, fatigue, sweating, and possibly severe pain. Patients should be informed of this prior to tapering off dopamine agonists and be monitored regularly. If symptoms persist, it may be necessary to temporarily elevate the pramipexole dose.
Neuroblocker malignant syndrome
Abrupt discontinuation of dopaminergic therapy has been reported with symptoms suggestive of neuroblocker malignant syndrome (see [DOSAGE]).
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 research program for this product, 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 reductions, withdrawals, or changes in antiparkinsonian therapy.
Complications of fibrosis
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.
Reports of possible fibrotic complications, including peritoneal fibrosis, pleural fibrosis, and pulmonary fibrosis, have been received after the introduction of pramipexole hydrochloride tablets. Although the evidence is insufficient to establish a causal relationship between pramipexole and these fibrotic complications, the effects of pramipexole cannot be completely ruled out.
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 to 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).
Residues in excretions
Residues resembling intact pramipexole hydrochloride extended-release tablets have been reported in the excretions of some patients. If a patient reports such an observation, the physician should reassess the patient’s response to treatment.
Information for Patient Use Precautions
1. Dosing Instructions
Patients should be advised to take this product only as prescribed. If a dose is missed, a double dose is not recommended for the next dose.
It may be taken with or without food. If the patient experiences nausea, it is recommended that taking this product with food may reduce the incidence of nausea.
Swallow with water and do not chew, break or crush the product (see [DOSAGE AND ADMINISTRATION]).
Both pramipexole hydrochloride tablets and pramipexole hydrochloride extended-release tablets have the active ingredient pramipexole. Please ensure that patients do not take both Pramipexole Hydrochloride Tablets and Pramipexole Hydrochloride Extended-Release Tablets at the same time.
2. Sedative effects
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 combining this product with other sedative medications or alcohol consumption and concomitant medications that increase plasma levels of this product (e.g., cimetidine).
3. Impulse control disorders and compulsive behavior
Patients and their caregivers should be alert to the possibility of compulsive shopping, pathological gambling, increased sexual desire, overeating, and/or other compulsive behaviors that the patient cannot control after taking this product.
4. Hallucinations
Patients should be informed of the possibility of hallucinations and that older patients with Parkinson’s disease are at higher risk than younger patients with Parkinson’s disease.
5. Postural (upright) hypotension
Patients may experience postural (upright) hypotension, which may be accompanied by dizziness, nausea, fainting or blackness, and sometimes sweating or no symptoms. Hypotension may occur more frequently during initial treatment. Therefore, patients should be cautioned not to stand up quickly after sitting or lying down, especially if they have been in this position and at the beginning of treatment with this product (see [Precautions]).
6. Pregnancy
Because the teratogenic potential of pramipexole has not been fully established in experimental animals and because of the limited experience with human use, patients should inform their physician if they become pregnant or plan to become pregnant during treatment.
7. Lactating women
Since pramipexole may be secreted through breast milk, patients should inform their physicians if they plan to breastfeed or are breastfeeding their infants.
Laboratory testing
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, this product is not recommended for use in children and adolescents under 18 years of age. There are no relevant applications for this product in the pediatric population with Parkinson’s disease.
[Geriatric Use].
Subjects older than 65 years of age have an approximately 30% lower total clearance of oral doses of this product 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 the placebo-controlled trial, 259 patients with early Parkinson’s disease, 47% were greater than or equal to 65 years of age. Hallucinations were more commonly seen in elderly patients taking this product, with an incidence of 13% in patients greater than or equal to 65 years of age and 2% in patients less than 65 years of age.
Drug Interactions]
Plasma Protein Binding
The degree of plasma protein binding is very low (<20%) and little biotransformation is seen 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-secreting transport system. Therefore, inhibitors of the renal clearance pathway of the active ingredient, or drugs cleared by this pathway, such as cimetidine and amantadine, as well as mexiletine, zidovudine, cisplatin, quinine, and procainamide may interact with this product, resulting in reduced 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 unhelpful in detoxification.
[Clinical Trials].
Parkinson’s disease.
In controlled clinical trials, the efficacy of this product lasted for approximately 6 months throughout the course of the trial. In open trials lasting more than 3 years, there was no reduction in efficacy.
In double-blind clinical trials, the efficacy and tolerability of overnight switching from pramipexole hydrochloride tablets to this product at the same daily dose was previously evaluated in patients with early Parkinson’s disease. The efficacy was observed to be maintained in 87 of 103 patients who switched, with no change in dose in 82.8% of 87 patients, an increase in dose in 13.8% and a decrease in dose in 3.4%. half of the 16 patients did not achieve a UPDRS II+III score for maintenance of efficacy, and the change from baseline was not clinically relevant. One patient who switched to this product experienced drug-related adverse effects leading to discontinuation of the drug.
[Pharmacology and Toxicology].
Pharmacodynamic properties
It is a dopamine receptor agonist that binds with high selectivity and specificity 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.
In vitro studies have demonstrated the ability to protect neurons from levodopa-induced neurotoxicity.
A dose-dependent reduction in prolactin was observed in volunteers. In a clinical trial in healthy volunteers, increased blood pressure and increased heart rate were seen using a faster than recommended approach (from weekly to every three days) with gradual increments to 4.5 mg/day. No such conditions were observed in patient studies.
Preclinical Safety Data
Repeated dose toxicity studies have demonstrated functional effects, primarily involving the central nervous system in rats and the reproductive system in female rats, which may result from amplified pharmacodynamic effects of the drug.
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 was not teratogenic in rats and rabbits, but had toxic effects on rat embryos at maternally toxic doses. The effects of this drug on pregnancy and female rat fertility have not been fully elucidated due to its prolactin-reducing effects and the specific effects of prolactin on reproductive function in female rats.
Delayed sexual development (i.e., foreskin separation and vaginal opening) was found in rat studies. The effects on humans are unknown.
The product is not genotoxic. In a carcinogenicity test, male rats developed testicular mesenchymal cell hyperplasia and adenomas, 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%.
The maximum plasma concentration is reached approximately 6 hours after administration. Concomitant eating does not usually affect the bioavailability of this product. Ingestion of a high-fat meal induces a 20% increase in peak concentration (Cmax) as well as a 2-hour delay in reaching peak concentration. However, this change is not clinically relevant.
The product shows linear kinetics with minimal inter-patient variation in plasma levels.
In humans, plasma protein binding 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
Room temperature, airtight storage.
Package】
Double aluminum packaging (polyamide/aluminum/polyvinyl chloride cold pressed solid pharmaceutical composite hard tablets, pharmaceutical aluminum foil), 7 tablets/plate x 1 plate/box.
Expiration date
24 months
【Execution standard
Approval number】
【Drug marketing license holder
Name: Hesco Pharmaceutical (Meishan) Co.
Registered address: No. 53, Shunjiang Avenue South, East District, Meishan Economic Development Zone, Sichuan Province
Manufacturer
Company Name: Hesco Pharmaceutical (Meishan) Co.
Production Address: No. 53, Shunjiang Avenue South, East District, Meishan Economic Development Zone, Sichuan Province
Postal code: 620000
Telephone number: 028-38787378
Fax number: 028-38787272
Web
Address: www.haisco.com