MIDODRINE 5 MG TABLETS - summary of medicine characteristics

Midodrine 5mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 5 mg midodrine hydrochloride.

Excipients with known effect:

Each tablet contains 0.1 mg Sunset Yellow FCF aluminium lake (E110).

For the full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Light orange coloured, round, scored tablets debossed with ‚H‘ above the score and ‚P‘ below the score on one side and ‚505‘ on the other side. The diameter of the tablet is 7.10 mm ±0.2 mm.

The tablet can be divided into equal doses.

4.1 Therapeutic indications

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

4.2 Posology and method of administration

Posology:

The usual initial dosage 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. The maintenance dosage should be determined individually for each patient to achieve optimal therapeutic effect while reducing the impact of adverse reactions.

The maximum daily dosage is 30 mg midodrine hydrochloride, divided into 3 single doses and this limit can be exceeded only in exceptional cases.

Midodrine 5 mg tablets should be taken during daytime when the patient performs his daily activities in 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. Blood pressure in supine and sitting position should be regularly monitored at the beginning of the treatment (at least twice a week). Treatment with Midodrine 2.5 mg tablets should be stopped if supine hypertension is significantly excessive.

Midodrine 5 mg tablets should be taken with sufficient amount of fluid. They can be taken during meal time. The duration of treatment is based on the progression of the disease.

Special populations

Pediatric population

Not recommended for children.

Elderly patients

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 or is considered clinically significant.

Patients with renal impairment

No specific studies addressing a possible dose-reduction have been performed in patients with renal insufficiency. Generally, 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.

4.3 Contraindications

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

4.4 Special warnings and precautions for use

Regular monitoring of blood pressure in supine and sitting position is required during treatment with midodrine tablets. 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 tablets. Hence, special caution is recommended.

Any possible danger to the patients should be ruled out before starting treatment with midodrine tablets. The patients should be informed to report any symptoms of supine hypertension such as palpitations, headaches, blurred vision to the attending physician and the patient should be advised to discontinue the medication immediately.

The dosage should be adjusted in this case or treatment with midodrine hydrochloride should be terminated. 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).

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 case of long-term treatment with midodrine tablets. Sufficient data is not available for patients with hepatic impairment. Therefore, it is advisable to monitor the liver function before and during treatment with midodrine tablets.

4.5 Interaction with other medicinal products and other forms of interaction Midodrine hydrochloride is a cytochrome P450 CYP2D6 inhibitor and can therefore influence the metabolism of other medicines (eg., Perphenazine, Amiodarone, Metoclopramide), which are metabolized through this cytochrome 450 isoenzyme. This may lead to increased systemic exposure and increased effects of this medicinal product.

4.6 Fertility, pregnancy and lactation

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 human milk. A risk to the newborns/infants cannot be excluded. Midodrine should not be used during breast-feeding.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

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.

4.9 Overdose

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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Cardiac stimulants, excluding cardiac glycoside.

ATC-Code: C01CA17

Mechanism of action

The alpha sympathomimetic drug midodrine hydrochloride is a prodrug, which is converted to its pharmacologically active metabolite desglymidodrine in various tissues.

Pharmacodynamic reactions

Desglymidodrine is a selective alpha-1-adrenoreceptor agonist. Its effect on cardiac circulation system is mainly due to increase of systolic and diastolic blood pressure. This increase in blood pressure occurs due to arterial and venous vasoconstriction. Midodrine hydrochloride triggers alpha receptors at the bladder, which in turn is connected with increase of tone at bladder exit and delayed emptying of the bladder.

5.2 Pharmacokinetic properties

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 (Cmax approx. 0.01 mg/l, tmax < 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 Cmax 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 Cmax 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 (tmax = 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 (t1/2 = 0.41 – 0.49 h), and desglymidodrine is eliminated somewhat slowly (t1/2 = 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.

5.3 Preclinical safety data

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.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Hydrophobic Colloidal anhydrous Silica

Microcrystalline cellulose

Pregelatinized Starch

Magnesium stearate

Sunset yellow FCF-Lake (E110)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

As packaged for sale: 2 years

For HDPE bottle after first opening: 100 days.

6.4 Special precautions for storage

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

For blister pack: Store below 250C

6.5 Nature and contents of container

Midodrine 5 mg tablets are available in pack sizes containing 100 × 1 tablets in PVC/PVDC/Aluminium perforated unit dose blisters.

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

6.6 Special precautions for disposal No special requirements.

7 MARKETING AUTHORISATION HOLDER

Tillomed Laboratories Limited

220 Butterfield, Great Marlings

Luton, LU2 8DL

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 11311/0657

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

09/04/2021