Midorine Tablets P.L.

Each tablet contains 2.5 mg Midodrine hydrochloride.
Excipients/Inactive Ingredients: Lactose, pregelatinized starch, povidone K-30, sodium starch glycolate, magnesium stearate, talc.

ATC Code: C01C1.
Pharmacology: Pharmacodynamics: Midodrine is the rapidly absorbed pro-drug of the pharmacologically active constituent desglymidodrine. Desglymidodrine is sympathomimetic with a direct and selective effect on the peripheral α1-adrenergic receptors inducing vasoconstriction of the venous system (reduction in the venous pool). The α-adrenergic effects of desglymidodrine are almost wholly attributable to the (-) enantiomer of desglymidodrine. After taking midodrine (as a racemic mxture present in the tablets) (+) desglymidodrine is also formed, though this contributes almost nothing to the desired effect.
Desglymidodrine increases the peripheral arterial resistance, resulting in an increase of the arterial blood pressure. Only limited data is available on the long term effects of administering midodrine.
Stimulation of the α-adrenergic receptors of the bladder and the ureter increases the sphincter muscle tone.
Desglymidodrine has no β-adrenergic effects. 
Pharmacokinetics: Absorption: After oral administration, midodrine is rapidly absorbed. The peak plasma concentrations are reached after approximately 30 minutes, and the plasma concentration of the active metabolite, desglymidodrine, peaks after approximately 1 hour.
AUC and C_max increase proportionally to the doses in a dosage range of 2.5-22.5 mg. Administration with food increases the AUC by approximately 25% and the C_max decreases by approximately 30%. The pharmacokinetics of desgylmidodrine is not affected. 
Distribution: Midodrine and desglymidodrine bind for less than 30% to plasma proteins. Studies on animals show that desglymidodrine is distributed in the target organs. Records are made of diffusion across the blood-brain barrier, the placenta and the human milk.
Metabolism: Midodrine is partially hydrolised before absorption (in the intestines), and partially after absorption (in plasma) by the seapration of glycine, herewith generating the active metabolite, desglymidodrine. The elimination of desglymidodrine is primarily caused by an oxidating metabolism, followed by (partial) conjugation.
Excretion: Midodrine (8%), desglymidodrine (40%), and their degradation products (55%) are excreted in the urine within 24 hours in conjugated or non-conjugated form. The plasma elimination half-life for midodrine is approximately 30 minutes, and is approximately 3 hours for desglymidodrine. Elimination of the active (-) enantiomer of desglymidodrine is slower than the elimination of the inactive (+) enantiomer.
Toxicology: Preclinical Safety data: Pharmacology safety studies and toxicity studies with animals did not show any indications of a safety risk for humans after repeated administration. Studies on animals are inadequate to determine the effects on the reproduction system.
In carcinogenic trials in rats a heightened tumour incidence in the testicular interstitial cells was observed; the relevance of this for humans is however unclear. The results of the micro-nuclei tests in rats also show that the genotoxicity of midodrine cannot be ruled out.

The treatment of symptomatic orthostatic hypotension due to autonomic dysfunction when corrective factors have been ruled out and other forms of treatment are inadequate.

Initial dose: 2.5 mg two to three times a day. Depending on results of supine and standing blood pressure recordings, this dosage can be increased weekly up to a dose of 10 mg three times a day. Higher dosages have not been studied.
It is essential to individually adjust the dosage to achieve a correct balance between the therapeutic effects and the possible risks.
No data is available regarding the use in children, elderly and in patients with impaired hepatic or renal function (see Contraindications).
The last daily dose should be taken at least 4 hours before bedtime in order to prevent supine hypertension (see also Precautions).
Midodrine may be taken with food (see Pharmacology: Pharmacokinetics under Actions).

In the event of an overdose hypertension and bradycardia (reflex-bradycardia) might be induced. Urine retention has been reported. Measure to prevent any further absorption of the drug from the gastro-intestinal tract should be considered. In the event of severe hypertension an alpha-sympatholytic agent like phentolamine can counteract the alpha-1-adrenoceptor agonist actions of the drug. The degradation product desglymidodrine is dialyzable.

Hypersensitivity to the active substance or to any of the excipients.
Midodrine is contraindicated in patients with: Hypertension, bradycardia, urinary retention, ischaemic heart disease, congestive heart failure, cardiac conduction disturbances, narrow angle galucoma, serious obliterative blood vessel disease, cerebrovascular occlusions and vessel spasms, aortic aneurism, proliferative diabetic retinopathy, thyrotoxicosis, pheochromocytoma, severe renal insufficiency (creatinine clearance less than 30 ml/min.) and serious prostate disorder.

Supine hypertension: The most potentially serious adverse reaction associated with midodrine therapy is marked elevation of supine arterial blood pressure (supine hypertension). Systolic pressure of about 200 mmHg were seen overall in about 13.4% of patients given 10 mg of midodrine. Systolic elevations of this degree were most likely to be observed in patients with relatively elevated pretreatment systolic blood pressure (mean, 170 mmHg). Use of midodrine is not recommended in patients with initial supine systolic pressure above 180 mmHg. Sitting blood pressures were also elevated by midodrine therapy. It is essential to monitor supine and sitting blood pressures in patients maintained on midodrine.
Potential for supine and sititng hypertension: The potential for supine and sitting hypertension should be evaluated at the beginning of midodrine therapy. Supine hypertension can often be controlled by preventing the patient from becoming fully supine (ie, sleeping with the head of the bed elevated). The patient should be cautioned to report symptoms of supine hypertension immediately. Symptoms may include cardiac awareness, pounding in the ears, headache, blurred vision, etc. The patient should be advised to discontinue the medication immediately if supine hypertension persists.
Slight slowing of the heart rate: A slight slowing of the heart rate may occur after administration of midodrine, primarily due to vagal reflex. Caution should be exercised when midodrine is used concomitantly with cardiac glycosides (eg, digitalis), psychopharmacologic agents, beta blockers or other agents that directly or indirectly reduce heart rate. Patients who experience any signs or symptoms suggesting bradycardia (pulse slowing, increased dizziness, syncope, cardiac awareness) should be advised to discontinue midodrine and should be reevaluated.
Renal function impairment: Midodrine use has not been studied in patients with renal impairment. Because desglymidodrine is eliminated via the kidneys and higher blood levels would be expected in such patients, midodrine should be used with caution in patients with renal impairment, with a starting dose of 2.5 mg. Renal function should be assessed prior to initial use of midodrine.
Hepatic function impairment: Midodrine use has not been studied in patients with hepatic impairment. Midodrine should be used with caution in patients with hepatic impairment, as the liver has a role in the metabolism of midodrine.
Special risk: Patients with urinary retention problems: Use cautiously in patients with urinary retention problems, as desglymidodrine acts on the alpha-adrenergic receptors of the bladder neck.
Orthostatic hypotensive patients: Use with caution in orthostatic hypotensive patients who are also diabetic, as well as those with a history of visual problems who are also taking fludrocortisone acetate, which is known to cause an increase in intraocular pressure and glaucoma.
Effects on Ability to Drive and Use Machine: No data is available with regard to this.

Pregnancy and Lactation: Pregnancy risk category: C
Data on the use of Midodrine in pregnant women are inadequately available. Also the experimental research on the effects of the medication on pregnancies, foetal development, delivery and postnatal development is inadequate.
Use during pregnancy is not recommended. No human data is available on use during lactation. Excretion into the breast milk was confirmed in animal experiments. The therapeutic effect on the mother needs to be weighed against the risk to the infant.

Very common (10%): Chills and pilo-erection (goosebumps); paresthesia, mainly of the scalp, supine hypertension (dose-dependent).
Common (1-10%): Urinary retention, headache.
Uncommon (0.1-1%): Nausea/dyspepsia, urinary urgency.
Rare (0.01-0.1%): Palpitations, tachycardia, bradycardia, restlessness, excitability and irritability.
Very rare: (<0.01%): Ventricular arrythmia.

Concomitant treatment with sympathomimetics and other vasoconstrictive substances such as reserpine, guanethidine, tricyclic antidepressants, antihistamines, thyroid hormones and MAO-inhibitors should be avoided as a pronounced increase in blood pressure may occur.
As with other specific α-adrenergic agonists, the effect of midodrine is blocked by α-adrenergic blockers such as prazosine and doxazosine and vice versa.
Simultaneous use of digitalis preparations is not recommended, since the bradycardia which occurs as a result of the use of midodrine is then potentiated and heart block may occur.
Midodrine may potentiate the hypertensive effects of fludrocortisone acetate.
Monitoring is recommended if midodrine is combined with other drugs that directly or indirectly reduce the heart rate.

Incompatibilities: Not applicable.

Do not store above 30°C. Protect from light.
Shelf-Life: 2 years

Vasoconstrictors

C01CA17 - midodrine ; Belongs to the class of adrenergic and dopaminergic cardiac stimulants excluding glycosides. Used in the treatment of hypotension.

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