Approval date: March 7, 2007
Date of revision: July 28, 2008
October 9, 2013
November 8, 2013
Midodrine Hydrochloride Tablets Instructions
Please read the instructions carefully and use under the guidance of your physician
WARNING: Because midodrine hydrochloride can cause a significant increase in ambulatory blood pressure, it should be used only in patients whose lives remain severely disturbed after clinical care. In the treatment of symptomatic postural hypotension, the indication for the use of midodrine hydrochloride is mainly indicated by objective indicators.
If the systolic blood pressure rises, the patient benefits from the treatment, but the improvement in the patient’s ability to perform daily activities has not been fully demonstrated.
Drug Name
Generic Name: Midodrine Hydrochloride Tablets
Trade name: Gutron® (Gutron)
English Name: Midodrine Hydrochloride Tablets
Hanyu Pinyin：Yansuan Miduojun Pian
Ingredients
Main ingredient: Midodrine Hydrochloride
Chemical name: 1-(2,5-dimethoxyphenyl)-2-glycinamide-ethanol-(1)-hydrochloric acid
Chemical structure formula.
Molecular formula: C12H19N2O4CI
Molecular weight: 290.75
Properties]: This product is a white tablet
Indications
For the treatment of postural hypotension. Only for those whose lives are still severely disturbed after clinical care, including non-pharmacological treatment (e.g. medical assisted stockings), volume expansion and lifestyle changes.
Female stress urinary incontinence.
Specification】Tablet, 2.5mg per tablet.
【Dosage】.
This product can be taken with meals.
Hypotension: Treat according to the patient’s autonomic tone and responsiveness and adjust accordingly. The following doses are recommended: Adults and young adults (12 years of age and older): Start with a dose of 2.5 mg (1 tablet) 2-3 times daily. Depending on the patient’s response and ability to tolerate the drug, the dose may be increased at 3-4 day intervals to 10 mg 3 times daily. This product should be taken during the day when the patient needs to get up to perform daily activities. Recommended dosing times at 4-hour intervals are as follows: morning upright or before morning upright, midday and late afternoon (usually no later than 6:00 pm). Doses may also be given at 3-hour intervals if needed for symptom control, but this should not be done frequently. The incidence of severe and persistent recumbent hypertension is higher (approximately 45%) with a single dose of 20 mg given at one time. The maximum daily dose is 30 mg. Some patients can tolerate daily doses above 30 mg, but the safety and efficacy have not been systematically studied or confirmed.
Because of the risk of proneural hypertension, this product should be used only in patients with significant improvement in symptoms after initial treatment and should be monitored frequently for changes in prone and standing blood pressure and discontinued if prone blood pressure is excessively elevated.
Because deglycyrrhizinated midodrine is excreted by the kidneys, it should be used with caution in patients with abnormal renal function; although systematic studies are lacking, the recommended dose for initiation of this product in such patients is 2.5 mg.
Urinary incontinence: Adults take 2.5 mg (1 tablet) to 5 mg (2 tablets) two to three times daily. Usually the dose should not exceed 10mg per day and may be adjusted according to the patient’s condition under the guidance of an experienced physician.
To prevent recumbent hypertension, Midodrine Hydrochloride tablets should not be taken after dinner or within 4 hours before bedtime.
[Adverse Reactions].
In placebo-controlled clinical trials, common adverse reactions included: hypertension in the recumbent and seated positions, abnormal sensation and itching mainly on the scalp, cutaneous erect hair reaction (goose bumps), chills, urinary incontinence, urinary retention and frequency, heartburn, and stomatitis.
The occurrence of these events in the 3-week placebo-controlled trial is shown in the table below.
Adverse events
Placebo group
n=88 Midodrine hydrochloride group
n=82 Event Reported Cases Patient % Reported Cases Patient % Total Reported Cases 22 77 Sensory abnormalities 44.51518.3 Hair erection 1001113.4 Difficulty urinating 2001113.4 Pruritus 322.31012.2 Recumbent hypertension 40067.3 Chills 0044.9 Pain 50044.9 Rash 11.122.41 Including allergy and scalp Sensory abnormalities
2Including dyspareunia (1), dysuria (2), dysuria (1), urinary retention (5), urinary urgency (2)
3 including scalp pruritus
4Including patients presenting with recumbent hypertension
5 including abdominal pain and increased pain
Rare adverse reactions include: headache, head swelling, facial vasodilation, flushing, confusion, dry mouth, nervousness/anxiety and skin rash. Occasional adverse reactions include visual field defects, vertigo, skin irritation, insomnia, drowsiness, erythema multiforme, mouth sores, dry skin, dysuria, malaise, back pain, heartburn; nausea; gastrointestinal distress; flatulence and painful leg cramps; sleep disturbances, restlessness, excitement, irritability, reflex bradycardia, tachycardia, abdominal pain, vomiting, diarrhea, abnormal liver function, and elevated liver enzymes.
The most likely serious adverse reactions in Midodrine hydrochloride treatment are prone to hypertension. Hair movement reactions such as abnormal sensation, pruritus, hair erection and chills are associated with the effect of midodrine hydrochloride on alpha-adrenergic receptors on hair follicles. Urinary frequency, urinary urgency and urinary retention are associated with the action of midodrine hydrochloride on bladder neck alpha receptors.
Contraindications]
This product is contraindicated in patients with severe organic heart disease, acute renal disease, pheochromocytoma, hyperthyroidism, urinary retention, proliferative diabetic retinopathy, severe vascular occlusion or vasospasm, severe renal impairment, prostatic hyperplasia with increased residual urine volume, closed-angle glaucoma or known hypersensitivity to the components of this product. This product should not be used in patients with hypertension.
Precautions]
Close monitoring of blood pressure in the recumbent and seated positions is required during drug administration. The patient should be evaluated for possible prone and seated hypertension before starting treatment with this product. Recumbent hypertension can usually be prevented by prohibiting the patient from lying completely flat, i.e., sleeping in a head-high position. Patients should be alert for and promptly report symptoms of prone hypertension. The main symptoms include heart slamming sensation, ear pounding sensation, headache, and blurred vision. If recumbent hypertension persists, the patient should discontinue the medication promptly. The dose should be adjusted according to the situation or discontinued if necessary.
For long-term use of this product, renal function and blood pressure should be checked regularly.
Blood pressure changes should be monitored closely when this product is combined with other vasoactive drugs such as phenylephrine, ephedrine, dihydroergotamine, phenylpropanolamine, or pseudoephedrine.
The administration of this product may result in a mild slowing of the heart rate, mainly caused by the vagal reflex. The combination of this product with cardiac glycosides (e.g. digitalis), psychotropic drugs, beta-blockers or other drugs that directly or indirectly lower the heart rate should be carefully considered. Patients who develop signs and symptoms of bradycardia (slowed pulse, increased dizziness, syncope, feeling of heart attack) should be considered for discontinuation and reassessment.
This product should be used with caution in patients with urinary retention because deglycine midodrine acts on alpha-adrenergic receptors in the bladder neck.
This product should be used with caution in patients with postural hypotension in combination with diabetes mellitus.
This product should also be used with caution in patients taking fludrocortisone for visual impairment.
This is because fludrocortisone can cause increased intraocular pressure and glaucoma.
No studies have been reported on the use of this product in patients with renal impairment. The initial dose should be 2.5 mg (see Dosage and Administration) and renal function should be adequately evaluated prior to initiation.
The use of this product in patients with hepatic impairment has not been studied. Considering that Midodrine is metabolized by the liver, this product should be used with caution in patients with hepatic impairment.
Certain over-the-counter (OTC) medications, such as cold and flu medications and diet pills, may raise blood pressure, so drug synergy needs to be considered when combined with midodrine hydrochloride. (See Drug Interactions). Patients should be informed of the possibility of recumbent hypertension and should avoid taking this product regardless of the duration of recumbency. Patients should take this product for the last time 3-4 hours before bedtime to reduce the occurrence of recumbent hypertension at night.
Pregnant women and nursing mothers
Pregnancy: This product can increase embryo uptake and reduce fetal weight in rats and rabbits. The survival rate of rabbit embryos was reduced after administration of 13 times (rats) and 7 times (rabbits) the maximum human dose based on body surface area. There is a lack of relevant studies in pregnant women. Therefore, Midodrine should not be used in women during pregnancy. Treatment should be discontinued immediately if pregnancy occurs during treatment.
Teratogenic effects have not been observed in studies in rats and rabbits.
Lactating women: It is not known whether this product can be secreted into breast milk. Therefore, Midodrine should not be used during lactation.
Pediatric Use]
The safety and efficacy of this product in pediatric patients have not been established.
Geriatric use]
The blood concentrations of Midodrine and Deglycine Midodrine are similar in patients aged 65 years or older compared to those younger than 65 years, and in male and female patients, so no adjustment of the recommended dose is necessary.
Drug Interactions]
Midodrine is a cytochrome P450 CYP2D6 inhibitor and therefore may affect the metabolism of other drugs that are metabolized by this isoenzyme. This may result in increased systemic exposure and increased action of these drugs.
Avoid the combination of midodrine with vasoconstrictors, sympathomimetic antihypertensive drugs and other drugs that can raise blood pressure, as this may lead to excessive hypertension.
Concomitant use of midodrine and alpha- and beta-blockers (which reduce heart rate) requires close monitoring.
Concomitant use of digitalis preparations is not recommended and may enhance the bradycardia and possible conduction block that occurs with midodrine.
Midodrine may enhance the antihypertensive effect of glucocorticoid preparations.
The concomitant use of cardiac glycosides with this product may lead to bradycardia, AV block or arrhythmia.
Alpha-adrenergic receptor agonists (e.g., phenylephrine, dextroephedrine, ephedrine, phenylpropanolamine) may potentiate the antihypertensive effect of this product. Therefore, careful consideration should be given when combining this product with other drugs that cause vasoconstriction.
In cases treated with salt corticosteroids (e.g., fludrocortisone acetate) and requiring concomitant administration of midodrine, with or without salt supplementation. Blood pressure should be monitored to prevent recumbent hypertension, and the incidence of recumbent hypertension may be reduced by lowering the fludrocortisone dose or salt intake prior to treatment with this drug. alpha-Adrenergic blocking drugs such as prazosin, terazosin, and doxazosin antagonize the effects of this drug.
Potential drug interactions: Deglycine Midodrine has a high renal clearance, which may be related to the active secretion function of the renal tubules for bases. This function of the renal tubules is also associated with the secretion of metformin, cimetidine, ranitidine, procainamide, aminoglutethimide, flucarbamide, and quinidine. Therefore it is likely that this product has drug-drug interactions with these drugs. However, this speculation is not yet supported by definite trial data.
Overdose]
Symptoms of overdose include hypertension, erectile hair (goose bumps), chills, and urinary retention. Two cases of overdose have been reported, both in young male patients. In one case, systolic blood pressure exceeded 200 mmHg after taking Midodrine hydrochloride 250 mg drops and was treated with 20 mg of intravenous phentolamine and was discharged the same day without complaints of discomfort. Another case took 205mg of midodrine hydrochloride (5mg tablets totaling 41 tablets)
After that, drowsiness, inability to speak, non-response to voice, response to painful stimuli only, and hypertension occurred, and after gastric lavage, the patient recovered completely the next day with no sequelae. No single dose value is known that can show overdose symptoms or be life-threatening. The LD50 of oral dose is about 30~50mg/kg in rats, 675mg/kg in mice, 125~160mg/kg in dogs.
The metabolite deglycine Midodrine can be dialyzed out.
Based on the pharmacological properties of this drug, general management after overdose includes induction of vomiting, and the use of alpha sympathetic blockers (e.g., phentolamine).
Bradycardia and bradycardia conduction defects can be counteracted by atropine.
Pharmacology and Toxicology
Mechanism of action: The product forms an active metabolite in the body, deglycine midodrine, which is an α1-adrenoceptor agonist, and can cause vasoconstriction through excitation of arterial and venous α-adrenoceptors, thereby increasing blood pressure. Deglycine Midodrine does not agonize cardiac beta-adrenergic receptors and does not cross the blood-brain barrier and therefore does not affect the function of the central nervous system.
Systolic and diastolic blood pressure in the standing, sitting and lying positions can be increased in patients with postural hypotension of various causes. One hour after administration of Midodrine 10 mg, systolic blood pressure in the standing position increased by about 15-30 mmHg, and the effect lasted for 2 to 3 hours in some patients.
In patients with autonomic failure, this product does not affect their pulse rate in the standing and recumbent positions.
Carcinogenesis, Mutagenesis, Fertility Impairment: In a long-term study in rats and mice administered at 3 to 4 times the maximum recommended human dose (based on body surface area of mg/m2), no carcinogenic effects were observed. No mutagenic effects were observed in mutagenicity studies. No impairment of fertility was observed in post-lethal studies in male mice. Other studies on the effect of this product on fertility have not been conducted.
Pharmacokinetics]
It is a precursor drug, and the drug effect after oral administration of Midodrine depends on the in vivo concentration of its active metabolite, monodeglycine Midodrine. It is rapidly absorbed after oral administration, with a peak time of about 30 minutes and a half-life of about 25 minutes for the precursor drug in the blood, and a peak time of about 1-2 hours and a half-life of about 3-4 hours for the active metabolite.
The maximum plasma concentration (Cmax) of midodrine is reached within 30 minutes after oral administration of 2.5 mg at approximately 0.01 mg/L. After oral administration of 5-10 mg of midodrine on an empty stomach in patients with upright hypotension, peak plasma concentration (0.027 mg/L) is reached at approximately 1 hour with deglycyrrhizinated midodrine.
The AUC and Cmax increased proportionally over the dose range 2.5-22.5 mg.
The absolute bioavailability of midodrine (assayed levels of deglycine midodrine) was 93%. Similar amounts of deglycine midodrine were formed after oral and intravenous administration. The AUC increases by approximately 25% with postprandial administration, while the Cmax decreases by approximately 30%. The pharmacokinetics of desglycine midodrine are not affected. Protein binding of either midodrine or desglycine midodrine is low.
Available studies have found that many tissues can deglycosylate midodrine to form deglycosylated midodrine, and both products are partially metabolized from the liver. Neither midodrine nor deglycine midodrine is a substrate for monoamine oxidase. Renal excretion of Midodrine is minimal. The renal clearance of desglycine midodrine is approximately 385 mL/min and most of it is excreted approximately 80% by the active secretory function of the renal tubules. The mechanism of action of this active secretion is not known, but it may be through the base secretion pathway, which is also responsible for the secretion of other base drugs (see Potential Drug Interactions).
Storage
Must be kept below 25℃, protected from light and stored in a dry place.
Packaging
Aluminum foil package, 10 tablets and 20 tablets per box.
Expiration date】 24 months
Execution Standard】Imported drug registration standard JX20130199
Approval Number】Imported Drug Registration Certificate No.: H20130782
Manufacturer
Company Name: Takeda Austria GmbH
Birth
Address: St. Peter-Straβe 25 AT-4020, Linz
Postal Code: AT-4020
Tel: +43-73269190
Fax: +43-73269194373
Web
Address: http://www.takeda.com
Production
Production
Factory: Takeda GmbH, Plant Oranienburg
Location
Address: Lehnitzstrαβe 70-98, 16515 Oranienburg, Germany