4.1. Therapeutic indications

Midodrine 2.5 mg tablets are indicated in adults for the treatment of severe orthostatic hypotension due to autonomic dysfunction when corrective factors have been ruled out and other forms of treatment are inadequate.

4.2. Posology and method of administration

Posology

Initial dose: 2.5 mg three times a day. Depending on the results of supine and standing blood pressure recordings, this dose may be increased weekly up to a dose of 10 mg three times a day. This is the usual maintenance dosage.

A careful evaluation of the response to treatment and of the overall balance of the expected benefits and risks needs to be undertaken before any dose increase and advice to continue therapy for long periods.

The last daily dose should be taken at least 4 hours before bedtime in order to prevent supine hypertension (see also section 4.4).

Midodrine 2.5 mg tablets may be taken with food (see section 5.2).

Paediatric population

The safety and efficacy of midodrine in children have not been established. No data are available.

Elderly population

There is limited data on dosing in the elderly and there are no specific studies which have focused on a possible dose reduction in the elderly population. Cautious dose titration is recommended.

Patients with renal impairment

There are no specific studies that have focused on a possible dose reduction in patients with renal impairment. Typically, midodrine is contraindicated in patients with acute renal impairment and severe renal impairment (see section 4.3).

Patients with hepatic impairment

There are no specific studies in this patient population (see also section 4.4).

Method of administration

For oral use.

4.3. Contraindications

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

- Severe organic heart disease (e.g. bradycardia, heart attack, congestive heart failure, cardiac conduction disturbances or aortic aneurysm).

- Hypertension.

- Serious obliterative blood vessel disease, cerebrovascular occlusions and vessel spasms.

- Acute kidney disease

- Severe renal impairment (creatinine clearance of less than 30 ml/min).

- Serious prostate disorder.

- Urinary retention.

- Proliferative diabetic retinopathy.

- Pheochromocytoma.

- Hyperthyroidism.

- Narrow angle glaucoma.

4.4. Special warnings and precautions for use

Severe orthostatic hypotension with supine hypertension

Regular monitoring of supine and standing blood pressure is necessary due to the risk of hypertension in the supine position, e.g. at night. Patients should be told to report symptoms of supine hypertension immediately such as chest pain, palpitations, shortness of breath, headache and blurred vision, and should be monitored for these side effects by the treating physician. Supine hypertension may often be controlled by an adjustment to the dose. If supine hypertension occurs, which is not overcome by reducing the dose, treatment with midodrine must be stopped.

The time of administration of the drug is important in this context. Avoid administration in the late evening. The last daily dose should be taken at least 4 hours before bedtime in order to prevent supine hypertension. The risk of supine hypertension occurring during the night can be reduced by elevating the head.

Severe disturbances of the autonomic nervous system

In patients suffering from a severe disturbance of the autonomic nervous system, administration of midodrine may lead to a further reduction of blood pressure when standing. If this occurs, further treatment with midodrine should be stopped.

Atherosclerotic disease

Caution must be observed in patients with atherosclerotic disease especially with symptoms of intestinal angina or claudication of the legs.

Prostate disorders

Caution is advised in patients with prostate disorders. Use of the drug may cause urinary retention.

Renal and hepatic function

This medicinal product is contraindicated in patients with acute renal impairment or severe renal impairment (see section 4.3). Treatment with midodrine has not been studied in patients with hepatic impairment. It is therefore recommended to evaluate the renal and hepatic parameters before starting treatment with midodrine and on a regular basis.

Heart rate

Slowing of the heart rate may occur after midodrine administration, due to vagal reflex. Caution is advised when midodrine is used concomitantly with cardiac glycosides (such as digitalis preparations) and other agents that directly or indirectly reduce heart rate. Patients should be monitored for signs or symptoms suggesting bradycardia.

4.5. Interaction with other medicinal products and other forms of interaction

Sympathomimetics and other vasopressor agents

Concomitant treatment with sympathomimetics and other vasoconstrictive substances such as reserpine, guanethidine, tricyclic antidepressants, antihistamines, thyroid hormones and MAO-inhibitors, including treatments that are available without prescription, should be avoided as a pronounced increase in blood pressure may occur.

Alpha-adrenergic antagonists

As with other specific α-adrenergic agonists, the effect of midodrine is blocked by α-adrenergic antagonists such as prazosin and phentolamine.

Heart rate reducing drugs

Monitoring is recommended if midodrine is combined with other drugs that directly or indirectly reduce the heart rate.

Glycosides

Simultaneous use of digitalis preparations is not recommended, as the heart rate reducing effect may be potentiated by midodrine and heart block may occur.

Corticosteroid preparations

Midodrine may potentiate or enhance the hypertensive effects of corticosteroid preparations. Patients being treated with midodrine in combination with mineralocorticoids or glucocorticoids (e.g. fludrocortisone) may be at increased risk of glaucoma/increased intraocular pressure, and should be carefully monitored.

Potential pharmacokinetic interactions

The potential for pharmacokinetic interaction is limited as the metabolic pathways do not involve cytochrome P450 enzymes (see section 5.2). However, decreased clearance of medicinal products metabolised by CYP2D6 (e.g. promethazine) has been reported.

Potential effect of other drugs on midodrine

No studies to evaluate the effect of other drugs on the pharmacokinetics of midodrine or the active metabolite desglymidodrine have been conducted. In vitro data indicate that desglymidodrine is a substrate of CYP2D6. Concomitant administration of drugs that inhibit this enzyme (e.g. quinidine, paroxetine, fluoxetine and bupropion) may cause increased plasma levels of desglymidodrine with a potential risk of increased adverse events.

Potential effect of midodrine on other drugs

Midodrine is an inhibitor of CYP2D6 and may affect the metabolism of other drugs. This may be of clinical relevance for active substances that are mainly metabolized by CYP2D6, e.g. tricyclic antidepressants, beta blockers, selective serotonin reuptake inhibitors (SSRI), antiarrhythmics (including class 1A, 1B and 1C) and monoamine oxidase inhibitors (MAO-inhibitors) type B, especially if the active substance also has a narrow therapeutic index.

Falsely elevated plasma metanephrine

Patients taking midodrine may have falsely elevated plasma metanephrine as a result of analytical interference when measured by HILIC-based HPLC-MS/MS. This potential for interference should be considered in cases where patients taking midodrine require biochemical investigation for potential phaeochromocytomas and paragangliomas.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no data from the use of midodrine hydrochloride in pregnant women. Studies in animals have shown reproductive toxicity at maternally toxic doses.

Midodrine 2.5 mg tablets are not recommended during pregnancy and in women of childbearing potential not using contraception.

Breastfeeding

It is unknown whether midodrine and its metabolites are excreted in human milk.

A risk to newborns/infants cannot be excluded. Midodrine 2.5 mg tablets should not be used during breastfeeding.

Fertility

Animal studies are insufficient with respect to the assessment of fertility.

4.7. Effects on ability to drive and use machines

Midodrine 2.5 mg tablets have negligible influence on the ability to drive and use machines.

However patients who experience dizziness or light-headedness should refrain from driving or operating machinery

4.8. Undesirable effects

Summary of the safety profile

The most frequent and very common adverse reactions related to midodrine therapy are piloerection, pruritus of the scalp and dysuria.

Tabulated list of adverse reactions

Organ Class

Very Common

(> 1/10)

Common

(> 1/100, < 1/10)

Uncommon

(> 1/1,000, < 1/100)

Rare

(> 1/10,000, < 1/1,000)

Frequency not known (cannot be estimated from available data)

Psychiatric disorders

Sleep disorders

Insomnia

Anxiety

Confusional state

Nervous system disorders

Paraesthesia

Paraesthesia of the scalp

Headache

Restlessness

Excitability

Irritability

Cardiac disorders

Reflex bradycardia

Tachycardia

Palpitations

Vascular disorders

Supine hypertension (dose dependent effect)

Gastrointestinal disorders

Nausea

Dyspepsia

Stomatitis

Abdominal pain

Vomiting

Diarrhoea

Hepatobiliary disorders

Abnormal hepatic function

Raised liver enzymes

Skin and subcutaneous tissue disorders

Piloerection (goosebumps)

Pruritus of the scalp

Pruritus

Chills

Flushing

Rash

Renal and Urinary disorders

Dysuria

Urinary retention

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. 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

The symptoms of overdose are the same as experienced with side effects. The following in particular may occur: hypertension, piloerection (goosebumps) and feeling cold, bradycardia (reflex bradycardia) and urinary retention.

Treatment: In addition to the main general “life support” measures, induced vomiting and the administration of an α-sympatholytic agent (e.g. nitroprusside, phentolamine, nitrogylcerine) is recommended, based on the pharmacology of the drug.

Bradycardia and bradycardic conduction disturbances can be blocked by atropine.

The active metabolite desglymidodrine is dialysable