Midodrine 2.5 Tablets

For use in the treatment of severe orthostatic hypotension due to dysfunction of the autonomic nervous system when corrective factors have been ruled out.

Posology:

Adults:

The usual starting dose is 2.5 mg of midodrine hydrochloride 2-3 times daily. The dose should be increased at weekly intervals in small increments until an optimal response is obtained. Most patients are controlled at or below 30 mg daily given in divided doses. The maximum daily dose is 30 mg midodrine hydrochloride, given in divided doses. Doses in excess of 30 mg daily are not recommended.

The supine and standing blood pressure should be regularly monitored during initial treatment (at least twice a week). And the use of Midodrine should be stopped if supine hypertension is increases excessively. Dosing of Midodrine should occur during the daytime when the patient needs to be in an upright position. A dosing schedule of 3-4 hour intervals is suggested. The last dose should be taken at least four hours before bedtime to reduce the risk of supine hypertension.

Special populations

Elderly

Although there is no evidence to suggest that dosage requirements are different in the elderly, it is recommended that the initial dose used be small and that increases in dosage be titrated against the patients' clinical condition with caution.

The administration of midodrine should be stopped and the attending physician notified immediately if the blood pressure in either position increases above 180/100 mm Hg or is considered clinically significant.

Paediatric population

Not recommended for children.

Patients with renal impairment

No specific studies addressing a possible dose-reduction have been performed in patients with renal insufficiency. Midodrine is contraindicated in patients with acute renal disease and severe renal insufficiency (see section 4.3).

Patients with hepatic impairment

No specific studies have been performed in this patient population.

Method of administration:

Midodrine tablets should be taken with a sufficient amount of fluid. They can be taken during meal times.

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

• Hypertension

• Severe organic heart disease or congestive heart failure

• Thyrotoxicosis

• Pheochromocytoma

• Acute nephritis

• Acute renal disease

• Severe renal insufficiency (creatinine clearance <30 ml/min)

• Hypertrophy of the prostate gland with residual urine volume increased

• Proliferative diabetic retinopathy

• Urinary retention

• Hyperthyroidism

• Narrow angle glaucoma

• Obliterative or spastic vessel disease (e.g. cerebrovascular occlusions and spasms)

• Vasovagal hypotension

Regular monitoring of blood pressure in supine and sitting position is required during treatment with midodrine. The potential for supine and sitting hypertension should be evaluated at the beginning of midodrine therapy. Patients with diabetes mellitus who show high blood pressure levels in supine position due to underlying neurological disorders (diabetic autonomic neuropathy) may suffer from supine hypertension with midodrine. Hence, caution is recommended.

The patients should be cautioned to report any symptoms of supine hypertension immediately such as cardiac awareness (palpitations, chest pain and shortness of breath), headache, blurred vision etc, and the patient should be advised to discontinue the medication immediately. Patients with a history of cerebrovascular accidents (CVA) or known risk factors for CVA should be monitored closely. The supine hypertension may often be controlled by an adjustment in the midodrine dosage. Supine hypertension may also be controlled by elevation of the head. The treatment should not be continued in patients suffering from severely fluctuating blood pressure with midodrine tablets.

Patients taking midodrine should avoid concomitant use of other adreno- sympathomimetic drugs including over the counter remedies (see 4.5).

Great caution should be exercised in patients with mild to moderate renal insufficiency (creatinine clearance >30ml/min and <90ml/min).

Patients with persistent labile blood pressure after stabilisation on midodrine should discontinue treatment.

Slowing of the heart rate may occur after administration of midodrine, primarily due to vagal reflex, therefore great caution should be taken when using it together with other agents that directly or indirectly slow the heart rate (see also section 4.5) e.g. digitalis, beta blockers, psychopharmacologic agents (specifically tricyclic antidepressants, phenothiazines and atypical antipsychotics). Patients experiencing any signs or symptoms suggestive of bradycardia (pulse slowing, increased dizziness, syncope, cardiac awareness) should be advised to discontinue midodrine.

The use of midodrine in patients who have an increased risk of or suffer from glaucoma / increased intra-ocular pressure or who are treated with mineralocorticoids / fludrocortisone acetate (which may increase intra-ocular pressure) should be avoided or monitored very closely.

It is advisable to monitor the renal function and blood pressure in patients undergoing long-term treatment with midodrine.

Sufficient data is not available for patients with hepatic impairment. Therefore, it is recommended to monitor the liver function before and during treatment with midodrine.

Midodrine is an inhibitor of cytochrome P450 CYP2D6 and may therefore affect the metabolism of other medicines which are metabolised by this isoenzyme (e.g. perphenazine, amiodarone, metoclopramide). This may lead to increased systemic exposure and increased effects of these medicines.

Pregnancy

There are no data from the use of midodrine in pregnant women. Animal studies have shown reproductive toxicity (see section 5.3).

Midodrine is not recommended during pregnancy and in women of childbearing potential not using contraception. Any woman becoming pregnant during treatment should be withdrawn from the treatment immediately upon established pregnancy.

Breast-feeding

It is unknown whether midodrine/metabolites are excreted in breast milk. A risk to the newborns/infants cannot be excluded. Midodrine should not be used during breast-feeding.

Patients who experience dizziness or light headedness while receiving Midodrine should refrain from operating machinery.

The following frequency categories are used for the evaluation of side-effects:

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continuous monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Overdosage of midodrine produces piloerection, sensation of coldness, an urgent desire to empty the bladder, hypertension and bradycardia.

These effects can be counteracted by induced emesis and administration of alpha- sympatholytic drugs. In marked bradycardia, atropine may be given at its usual dose. In exanthema, H-1 antihistamines should be administered.

The active metabolite desglymidodrine is dialysable.

Pharmacotherapeutic group: Adrenergic and dopaminergic agents. ATC-Code: C01CA17

A directly - acting alpha sympathomimetic agent which enhances vascular smooth muscle tone leading to a pressor response after oral administration. The major biological activity resides in the main metabolite desglymidodrine.

A 6 week study with a 3 week double blind period of midodrine 10 mg t.i.d. (three times a day) versus placebo, in patients with orthostatic hypotension due to autonomic dysfunction indicated that midodrine significantly, increased standing systolic blood pressure and improved dizziness/unsteadiness compared to placebo.

Two open long-term studies have been conducted with Midodrine. 693 subjects with orthostatic hypotension from the Bradbury-Eggleston Syndrome (28%), from renal failure, syncope, autonomic neuropathy and AIDS (33%) and from other causes (39%), received an average total daily dose of midodrine 17-24 mg over periods up to one year. 52% completed one year of study.

The primary efficacy variables were the quality of life questionnaire evaluating the symptoms as indicated in the enclosed table, the improvement in standing blood pressure and the investigators global opinion. In the quality of life index (QOLI) all questions were answered using a three point scale; 1 = symptom occurred often, 2 = symptom occurred sometimes, 3 = symptom never occurred. At each visit the subject's blood pressure was measured before taking a dose of midodrine and one hour thereafter. The investigators global opinion was recorded at the end of the study. The investigator assessed the subject's ability to perform daily activities. Summary statistics only were provided.

The percentage change in the QOLI is indicated in the table. Improvement was seen in the standing blood pressure. The systolic blood pressure was increased by 12mm of mercury, while the diastolic blood pressure was improved by 6-7 mm of mercury. The investigator stated that at the end of the study 52% of subjects had good to excellent ability to perform daily activities.

It is important to note that subjects did continue to take previous medications including steroids.

102 subjects died during this long-term open-ended trial however none of the deaths was reported to be drug related. It is important to note that most of these patients had considerable impairment of cardiac function. The most common adverse events apart from deaths were headache in 5%, supine hypertension in 6%, piloerection in 5% and pruritus of the scalp in 10%.

There were no clinically significant effects of midodrine on laboratory test results or on the electrocardiogram.

In a second long-term study 723 patients with neurogenic orthostatic hypotension received an average total daily dose of 18 mg of midodrine over a one year period. Up to 196 patients took the medication for a period equal to or greater than one year.

The primary efficacy event was the change in standing blood pressure. The baseline systolic and diastolic pressures were the last measurements taken prior to the first dose of midodrine. End point systolic and diastolic pressures were the final measurements taken during treatment with midodrine. Summary statistics were provided.

At the end point the mean standing systolic blood pressure had increased by 8 mm of mercury from baseline with an increase in the diastolic blood pressure by nearly 5 mm of mercury.

It is important to note that subjects did continue to take previous medications including steroids.

There was a 6% death rate. In all cases the relationship to midodrine was judged as none or unlikely. The most common adverse events other than death reported in this study were syncope and scalp pruritus.

Absorption

After oral administration of a dose of 2.5 mg, midodrine hydrochloride is rapidly and completely absorbed and reaches its peak plasma concentrations after approximately 20-30 minutes (C_max approx. 0.01 mg/l, t_max < 30 min). The prodrug midodrine hydrochloride is converted in different tissues (also in liver) enzymatically into its active metabolite desglymidodrine. The absolute bioavailability of midodrine hydrochloride (and desglymidodrine) amounts to 93% after oral administration.

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 desglymidodrine is not affected.

After oral administration of a dosage of 5 – 10 mg of midodrine hydrochloride in fasting patients with orthostatic hypertension, desglymidodrine reaches its highest plasma concentration (0.027 mg/l) approx. 1h after oral administration (t_max = 1.1 h) and after intravenous injection within a period of 60 – 120 min.

Distribution

The distribution of midodrine in humans was not analysed.

Midodrine and desglymidodrine bind less than 30% to plasma proteins. Studies on animals show that desglymidodrine is distributed in the target organs. The distribution of midodrine in humans has not been established, it does not appear to cross the blood-brain barrier after oral administration.

Biotransformation

This medicinal product is split into its pharmacologically active metabolite desglymidodrine through enzymatic degradation in different tissues (including liver).

Elimination

Midodrine hydrochloride is quickly eliminated from plasma (t_1/2 = 0.41 – 0.49 h), and desglymidodrine is eliminated somewhat slowly (t_1/2 = 3 h).

Midodrine hydrochloride and desglymidodrine are almost completely (91%) eliminated renally within 24 hours (approx. 40 – 60% as active metabolite, 2 – 5% as non-metabolised midodrine hydrochloride, the rest as other pharmacologically inactive metabolites). The elimination of midodrine hydrochloride or desglymidodrine through faeces is negligible. After intravenous administration, 53% of applied quantity was eliminated in the first 4 hours and 47% through urine after peroral administration. The faecal elimination is 2.1%.

Special populations

To date there are no pharmacological data about midodrine or its metabolites desglymidodrine in older patients or patients with renal and/or liver function disorders.

Non-clinical data revealed no special hazard for humans based on conventional studies of safety pharmacology and repeated dose toxicity.

Reproduction toxicity

Studies in rats and rabbits have shown embryotoxicity, but no teratogenic effects are reported.

Genotoxicity

In-vitro and in-vivo studies for midodrine hydrochloride did not show any indication of mutagenic or genotoxic potential.

Carcinogenicity

Increased tumour incidence in the testicular interstitial cells was observed in carcinogenicity studies. The relevance of this observation for humans is not clear.

Hydrophobic Colloidal anhydrous Silica

Microcrystalline cellulose

Pregelatinized Starch

Magnesium stearate

Not applicable.

As packaged for sale: 3 years

For HDPE bottle after first opening: 100 days.

For HDPE bottle pack: This medicinal product does not require any special storage condition.

For blister pack: Store below 25° C.

Midodrine 2.5 mg tablets are available in pack sizes containing 30x1, 90x1 and 100 x 1 tablets in PVC/PVDC/Aluminium and OPA/Alu/PVC/Alu perforated unit dose blisters.

It is also available in High Density Polyethylene (HDPE) bottle pack with 100 tablets.

Not all pack sizes may be marketed.

No special requirements.