Orthostatic hypotension

Posology:
Orthostatic hypotension
Treatment should be conducted with adequate consideration of the patient’s tonus and the responsiveness of the patient’s autonomous nervous system and should be adjusted to individual requirements.
The following dosing guidelines are applicable:
Adults and juveniles (> 12 years):
Initial dose 2.5 mg 2-3 times daily.
This dosage may be increased depending on the patient’s response and tolerability at intervals of at least 3 to 4 days up to a maintenance dose of 10 mg three times daily.
Maximum daily dose: 30 mg.
Midodrine should be taken during daytime with the patient in upright position and pursuing his/her normal everyday activities.
The recommended dosing interval is 3-4 hours.
The first dose should be taken shortly before or after getting up in the morning, the second dose at noon and the third dose in the late afternoon.
For minimizing the risk of supine hypertension midodrine should not be taken after the evening meal or less than 4 hours before bedtime.
Special patient populations
Children younger than 12 years:
Considering the lack of experience use in children younger than 12 years is not recommended.
Elderly patients:
No specific studies regarding a potential dose reduction in elderly patients have been conducted.
Patients with impaired renal function:
No specific studies regarding a potential dose reduction in elderly patients have been conducted. Generally, midodrine is contraindicated in patients with acute renal disease or severe impairment of renal function (see section 4.3).
Patients with impaired hepatic or renal function:
No data available.
Method of administration:
For oral use
GUTRON 2.5 mg – Tablets are taken together with some fluid (e.g. a glass of water).

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. • Severe organic heart or vascular disease, arrhythmias. • Hypertension • Severe obliterative vascular disease or disorders associated with vascular spasms • Acute renal disease • Severe renal impairment • Prostatic hyperplasia with increased residual urine volume • Mechanical urinary outflow obstruction • Urinary retention • Proliferative diabetic neuropathy • Phaeochromocytoma • Hyperthyroidism • Narrow angle glaucoma • Pregnancy and lactation

During treatment supine, sitting and standing blood pressure is to be monitored at regular intervals.
The potential for supine or sitting hypertension should be evaluated when initiating treatment.
The patients should be advised of the symptoms suggestive of hypertension (cardiac awareness, headache, visual disturbances) and should be cautioned to discontinue treatment and notify their doctor immediately in any such cases.
Development of supine hypertension may often be avoided by an appropriate dose reduction.
Continual use is only recommended in patients having shown adequate response to initial treatment. Midodrine should be discontinued in the case of major fluctuations of blood pressure.
Concomitant use of sympathomimetics and other vasopressor agents such as reserpine, guanethidine, tricyclic antidepressants, antihistamines, thyroid hormones and MAO inhibitors should be avoided as a marked blood pressure increase may be experienced.
Bradycardia being essentially reflectory in nature may occur during treatment; therefore, caution is indicated with the concomitant use of medications directly or indirectly slowing the heart rate (e.g. digitalis, beta-blockers, psychopharmaceutical agents).
The patients are to be made aware of symptoms suggestive of bradycardia (e.g. slowed pulse, cardiac awareness, increased dizziness, loss of consciousness) and advised to discontinue treatment and notify their doctor immediately in such cases.
Patients with cor pulmonale require particularly careful supervision.
Caution is indicated in patients with glaucoma/increased intraocular pressure or increased risk for such conditions as well as in those with concomitant treatment with mineralocorticoids/fludrocortisone (because of the potential increase of intraocular pressure).
No data is available for the use in patients with impaired hepatic and renal function. Therefore, parameters of hepatic and renal function should be evaluated before starting treatment and monitored at regular intervals.
No data is available on the use in children below 12 years of age and in elderly patients.

Midodrine is an inhibitor of cytochrome P450 CYP2D6 and may therefore affect the metabolism of other drugs metabolised by this isoenzyme. This may lead to increased systemic exposure and increased effects of these drugs.
Concomitant use of sympathomimetics and other vasopressor agents such as reserpine, guanethidine, tricyclic antidpressants, antihistamines, thyroid hormones and MAO inhibitors should be avoided as marked increase of blood pressure may be experienced.
The effects of midodrine may be antagonised by alpha-adrenoceptor blockers (such as prazosine, phentolamine). Concomitant use of beta-adrenoceptor blockers may produce increased bradycardia. Close monitoring will be required.
Concomitant use of digitalis is not recommended, as the bradycardia occurring with the use of midodrine will be potentiated and may produce heart block.
Concomitant use of atropine and corticosteroids may cause enhanced or excessive blood pressure increase.

Pregnancy
Pregnancy Category C. Midodrine has been shown to have an embryocidal effect in rats and rabbits when given in doses (50) times the human dose. There are no adequate and well-controlled studies in pregnant women. Midodrine is contraindicated in women who are or may
become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
Breastfeeding
It is unknown whether midodrine or desglymidodrine is excreted in breast milk.
Therefore, midodrine must not be used while breastfeeding.

There are no studies on the effect of midodrine on reactivity and ability to drive. When driving a vehicle it should be considered that restlessness, excitability and irritability may be experienced occasionally.

Evaluation of adverse effects has been based on the following frequency categories:
Very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).
Psychiatric disorders
Uncommon: Sleep disorders, insomnia
Not known: Restlessness, confusion
Nervous system disorders
Common: Paraesthesia
Uncommon: Headache, restlessness, excitability and irritability
Cardiac disorders
Uncommon: Reflex bradycardia, palpitations
Rare: Tachycardia, ventricular arrhythmias
Vascular disorders
Common: Supine hypertension (blood pressure ≥ 180/110 mmHg) at a dosage of more than 30 mg daily
Uncommon: Supine hypertension (blood pressure ≥ 180/110 mmHg) at a dosage of up to 7.5 mg daily
Gastrointestinal disorders
Common: Nausea/dyspepsia, heartburn, stomatitis
Not known. Abdominal pain, vomiting, diarrhoea
Hepatobiliary disorders
Rare: Abnormal hepatic function tests, increase of hepatic enzymes
Skin and subcutaneous tissue disorders
Very common: Piloerection (goose pimples) (13%)
Common: Pruritus (mainly in head region), chills, flushing, skin rash
Renal and urinary disorders
Very common: Dysuria (13%)
Common: Urinary retention (6%)
Uncommon: Micturition disorders, urinary urgency
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
To report any side effect(s):
• Saudi Arabia:
The National Pharmacovigilance and Drug Safety Centre (NPC)
Fax: +966-11-205-7662
Call NPC at +966-11-2038222
Exts: 2317-2356-2353-2354-2334-2340.
Toll free phone: 8002490000
E-mail: npc.drug@sfda.gov.sa
Website: www.sfda.gov.sa/npc
• Other GCC States:
Please contact the relevant competent authority.

Symptoms
In the case of overdose the symptoms listed as adverse effects may occur in potentiated form, in particular hypertension, piloerection, chills, bradycardia and urinary retention.
Treatment of overdose
In addition to general measures of detoxification, induced vomiting and the use of alpha-sympatholytics (e.g. phentolamine, nitroglycerine) may be required.
Bradycardia and bradycardic arrhythmias may be treated with atropine (caution: blood pressure increase).
The active metabolite desglymidodrine is dialysable.

Pharmacotherapeutic group: Cardiac stimulants, excl. cardiac glycosides; adrenergic and dopaminergic agents, ATC-Code: C01CA17
Midodrine is a prodrug and is converted to the active substance desglymidodrine by enzymatic hydrolysis. Desglymidodrine selectively stimulates peripheral α1-adrenoceptors. It shows no activity on myocardial β-adrenoceptors.
This action is essentially consistent with that of other alpha-sympathomimetics.
This action is associated with an increase of systolic and diastolic blood pressure and with reflectory bradycardia.
The increase of blood pressure is primarily based on a constriction of smaller veins and – to a lesser extent – of the arterioles (increase of peripheral resistance).
Desglymidodrine causes a minor reduction of cardiac output and of renal blood flow.
The urinary bladder shows an increase of tone of the internal sphincter and thus a delay in voiding.

Absorption
Following oral dosing in healthy subjects midodrine is rapidly and almost completely absorbed.
In healthy subjects and patients with orthostatic hypotension, peak plasma levels of desglymidodrine are achieved after approximately 1 hour.
Absolute bioavailability (as desglymidodrine) after oral dosing is 93%.
Distribution
The distribution of midodrine has not been studied. Midodrine does not appear to cross the blood-brain barrier.
Following a dose of 2.5 mg peak plasma levels of 10 μg/l will be achieved within 30 minutes.
Biotransformation
Midodrine is converted to the active metabolite desglymidodrine by enzymatic hydrolysis in various tissues (including the liver).
Elimination
The plasma elimination half-life (t1/2β) of midodrine is 0.49 hours, that of the active metabolite 2-4 hours.
Midodrine and its metabolites are almost completely eliminated with the urine within 24 hours with about 40-60% eliminated as active primary metabolite, about 2-5% as unchanged midodrine and the rest as pharmacologically inactive metabolites.
Midodrine does not appear to cross the blood-brain barrier.
No kinetic data for elderly patients or those with impaired hepatic or renal function are available.

In addition to the pharmacological effects of midodrine, studies of repeated dose toxicity showed marked degenerative renal changes in rats and hepatic changes in rats and dogs at doses being the 12- to 50-fold (in mg/kg) of the maximum therapeutic dose in humans.
In preclinical studies, midodrine has been shown to be non-teratogenic and non-mutagenic.
In carcinogenicity studies in rats increased tumour incidence in testicular interstitial cells was seen; the relevance of this finding for humans is unknown.

Magnesium stearate
Talc
Colloidal anhydrous silica
Microcrystalline cellulose
Maize starch

Not applicable.

2 years

Store below 25°C.
Store in the original package in order to protect from light.

20 or 50 tablets in PVC/PVdC/Al blister packs

No special requirements.