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BRAMOX 5 MG TABLETS

Active substance(s): MIDODRINE HYDROCHLORIDE / MIDODRINE HYDROCHLORIDE

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Bramox 5 mg tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 5 mg of midodrine hydrochloride.
Excipients with known effect:
Each tablet contains 0.2 mg Sunset Yellow FCF (E110).
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Tablet.
Orange, round tablet of diameter 7 mm. Plain on one side with “MID” debossed
above the score line and “5” debossed below the score line on the other side.
The scoreline is only to facilitate breaking for ease of swallowing and not to divide
into equal doses.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Bramox 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 (Bramox 2.5 mg tablets are also available).
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).
Bramox 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
• 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.
• Hypersensitivity to the active substance or to any of the excipients listed in
section 6.1.

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 physican. 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 αadrenergic 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.

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.
Bramox 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. Bramox 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
Bramox 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)

Psychiatric
disorders
Nervous system
disorders

Paraesthesia
Paraesthesia
of the scalp
Headache

Cardiac
disorders
Vascular
disorders

Gastrointestina
l disorders

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

Sleep
disorders
Insomnia
Restlessness
Excitability
Irritability
Reflex
bradycardia

Supine
hypertension
(dose
dependent
effect)
Nausea
Dyspepsia
Stomatitis

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

Frequency
not known
(cannot be
estimated
from
available
data)
Anxiety
Confusional
state

Tachycardia
Palpitations

Abdominal
pain
Vomiting
Diarrhoea

Hepatobiliary
disorders

Skin and
subcutaneous
tissue disorders
Renal and
Urinary
disorders

Abnormal
hepatic
function
Raised liver
enzymes
Piloerection
(goosebumps
)
Pruritus of
the scalp
Dysuria

Pruritus
Chills
Flushing
Rash
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 (website: www.mhra.gov.uk/yellowcard).

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.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Cardiac Therapy, Adrenergic and dopaminergic agents
ATC-code: C01C A17
Midodrine is the rapidly absorbed pro-drug of the pharmacologically active
constituent desglymidodrine. Desglymidodrine is a sympathomimetic agent with a
direct and selective effect on the peripheral α1-adrenergic receptors. This α1stimulative effect induces vasoconstriction of the venous system (causing a reduction
in venous pooling). The α1-adrenergic effects of desglymidodrine are almost wholly
attributable to the (-) enantiomer of desglymidodrine. After taking midodrine, which
is a racemic mixture, (+) desglymidodrine is also present, though this contributes
almost nothing to the desired effect.
Desglymidodrine increases the peripheral arterial resistance, resulting in an increase
in arterial blood pressure.
Only limited data is available on the long-term effects of taking midodrine.
Stimulation of the α-adrenergic receptors of the bladder and the ureter increases the
sphincter muscle tone.
Desglymidodrine has no β-adrenergic effects.

5.2

Pharmacokinetic properties
Absorption
After oral administration, midodrine is rapidly absorbed. 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 Cmax increase proportionally to the dose across 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
are not affected.
Distribution
Neither midodrine nor desgylmidodrine are bound to plasma proteins to any
significant extent (less than 30%). Desglymidodrine diffuses poorly across the bloodbrain barrier. Diffusion across the placenta has been reported. It is not known whether
this drug is excreted in human milk.

Metabolism
Midodrine is partially hydrolysed before absorption (in the intestines), and partially
after absorption (in plasma) by the separation 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 by more than 90% within 24 hours in conjugated or nonconjugated forms. 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.

5.3

Preclinical safety data
Safety Pharmacology studies and repeat-dose toxicity studies with animals did not
show any indications of a safety risk for humans at therapeutic doses. Studies in the
rat and rabbit show that at maternally toxic doses, midodrine is embryotoxic. There is
no evidence of teratogenicity.
Midodrine is not genotoxic and after long term studies in rats (104 weeks) and mice
(78 weeks), there was no evidence that midodrine was carcinogenic at doses of up to
10 mg/kg/day and up to 15 mg/kg/day, respectively, compared to a maximum patient
daily dose of 30 mg (~0.5 mg/kg/day).

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Microcrystalline Cellulose
Maize Starch
Magnesium Stearate
Silica colloidal anhydrous
Sunset Yellow FCF (E110)

6.2

Incompatibilities
Not applicable.

6.3

Shelf life

3 years.
In-use shelf life for HDPE bottle pack: up to 8 weeks

6.4

Special precautions for storage

Store below 30°C.

6.5
Nature and contents of container
White, opaque, HDPE round bottle with blue polypropylene cap containing 100
tablets.
Carton of 100 tablets in aluminium/aluminium blister packs.
6.6

Special precautions for disposal
Any unused medicinal product or waste material should be disposed of in accordance
with local requirements.

7

MARKETING AUTHORISATION HOLDER
Brancaster Pharma Limited
Church House
48 Church Street
Reigate, Surrey
RH2 0SN, United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 41542/0002

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
18/03/2015

10

DATE OF REVISION OF THE TEXT
14/12/2016

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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