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LEO Pharma

Cashel Road, Dublin 12,
Telephone: +353 1 490 8924
WWW: http://www.leo-pharma.ie
Medical Information Direct Line: +353 1 4908924
Medical Information e-mail: medical-info.ie@leo-pharma.com
Medical Information Facsimile: Not Applicable


Summary of Product Characteristics last updated on medicines.ie: 31/10/2014
SPC Low Centyl K



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1. NAME OF THE MEDICINAL PRODUCT

Low Centyl® K 1.25 mg/573 mg modified-release tablets


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2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 1.25 mg of bendroflumethiazide and 573 mg of potassium chloride.

For the full list of excipients see section 6.1.


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3. PHARMACEUTICAL FORM

Modified release tablet.

Light yellow film-coated oval shaped modified release coated tablet.


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4. CLINICAL PARTICULARS

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4.1 Therapeutic indications

Indications for use:

In the management of hypertension alone or in combination with other antihypertensives.


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4.2 Posology and method of administration

Posology

Adults: Hypertension: 1 tablet daily.

Method of administration

For oral administration.

The tablets should be taken with or after meals with at least a full glass of water or fluid (see section4.4).


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4.3 Contraindications

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

• Addison's disease.

• Severe renal impairment or anuria (see section 4.4)

• Severe hepatic impairment (see section 4.4)

• Established arthritis urica

• Severe dehydration electrolyte imbalance including hypercalcaemia, hyponatraemia, hyperchloraemia, hyperkalaemia or any situation which might lead to hyperkalaemia.

• Ulcer or obstruction of the gastrointestinal tract.


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4.4 Special warnings and precautions for use

Bendroflumethiazide is a sulphonamide, which should be considered by prescribers in relation to hypersensitivity.

Thiazide diuretics should be used with caution in patients with mild or moderate renal or hepatic impairment and in patients with potential obstruction of the urinary tract (see section 4.3).

With long-term treatment, potassium blood levels should be monitored and consideration should be given to fluid and electrolyte status especially in elderly patients. Depending on the results, potassium containing food or extra potassium supplementation might need to be recommended.

Thiazides may provoke hyperglycaemia and glucosuria in diabetic and other susceptible patients. In case of reduced glucose tolerance, adjustment of the anti-diabetic dose may be necessary (see section 4.5).

Thiazide diuretics should be used with caution in hypotensive patients.

Thiazides may cause hyperuricaemia and precipitate or aggravate attacks of gout.

Thiazides may cause exacerbation or activation of systemic lupus erythematosus.

Thiazide diuretics found in urine by doping test is cause for disqualification of athletes.

Concomitant use of thiazides and lithium should be avoided (see section 4.5). Concomitant therapy requires close monitoring of serum lithium levels. If combination is still required, then lower lithium doses may be appropriate.

Potassium chloride should be administered with considerable care to patients with cardiac disease or conditions predisposing to hyperkalaemia such as renal or adrenocortical insufficiency, acute dehydration, or extensive tissue destruction as occurs with severe burns. Serum potassium should be monitored in patients with cardiac or renal impairment.

Potassium chloride may induce ulceration of the gastrointestinal tract in particular the small bowel. Potassium chloride should be administered with caution to patients in whom passage through the gastro-intestinal tract may be delayed. Treatment should be discontinued if severe nausea, vomiting, or abdominal distress develops.

The tablets should be taken with or after meals with at least a full glass of water or fluid (see section 4.2).


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4.5 Interaction with other medicinal products and other forms of interaction

Lithium

Bendroflumethiazide reduces lithium clearance resulting in increased lithium concentrations in serum and risk of lithium toxicity (weakness, tremor, excessive thirst, confusion) (see section 4.4). Concomitant therapy requires close monitoring of serum lithium levels. If combination is still required, then lower lithium doses may be appropriate.

NSAIDs

Non-steroidal anti-inflammatory drugs (NSAIDs) antagonise the diuretic effect of bendroflumethiazide by decreasing renal prostaglandin production. The effects of concurrent use should be monitored (e.g. blood pressure, signs of renal failure) and the dose of bendroflumethiazide modified if necessary. Diuretics may enhance the nephrotoxicity of NSAIDs.

Antiarrhythmics

Concomitant use of bendroflumethiazide and class Ic and III antiarrhythmic agents may result in increased risk of electrolyte imbalance and subsequent cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest). Patients should be monitored for electrolytes and symptoms of arrhythmias.

Digitalis glycosides

The hypokalaemic effect of bendroflumethiazide may enhance Na+-K+-ATPase inhibition by digitalis glycosides. Concomitant therapy may thus result in digitalis toxicity (nausea, vomiting, arrhythmias). Patients should be monitored for signs of potassium depletion. Potassium supplementation and lower digitalis glycoside dose should be considered.

Non-depolarising neuromuscular blocking agents

The hypokalaemic effect of bendroflumethiazide may enhance the neuromuscular blocking activity of non-depolarising muscle relaxants.

Beta-2 adrenergic agonists

The hypokalaemic effect of bendroflumethiazide may be enhanced by beta-2 adrenergic agonists.

Antihypertensives and drugs inducing postural hypotension

Bendroflumethiazide may potentiate the effect of antihypertensive agents and drugs inducing postural hypotension e.g. tricyclic antidepressants.

Drugs increasing potassium levels

Due to the content of potassium chloride concomitant treatment with drugs such as potassium-sparing diuretics, angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists increase the risk of hyperkalaemia.

Antidiabetics

Bendroflumethiazide can reduce the effects of the antidiabetics and impair the control of diabetes by raising blood glucose levels (see section 4.4). This effect appears to be dose related.

Calcium salts and drugs increasing calcium levels

Bendroflumethiazide can cause calcium retention by reducing its urinary excretion. Concomitant administration of calcium or any drugs that increase calcium levels may result in hypercalcemia.

Photosensitising agents

Co-administration of bendroflumethiazide and other drugs known to cause photosensitivity reactions may increase the severity of these reactions.

Bile-acid binding resins

Cholestyramine and similar drugs reduce the absorption of bendroflumethiazide


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4.6 Fertility, pregnancy and lactation

There are no adequate data from the use of bendroflumethiazide with potassium chloride in pregnant women. Animal studies are insufficient with respect to effects on pregnancy.

Thiazides cross the placenta and there have been reports of neonatal jaundice, thrombocytopenia, and electrolyte imbalance after maternal use. Reduction in maternal blood volume could also adversely affect placental perfusion.

Bendroflumethiazide should not be used during pregnancy unless clearly necessary.

Breastfeeding

Bendroflumethiazide is excreted in breast milk and should not be used during breastfeeding.

Fertility

There are no clinical studies with bendroflumethiazide regarding fertility.


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4.7 Effects on ability to drive and use machines

The medicinal product has no or negligible direct influence on the ability to drive and use machines. However, the patient should be informed that dizziness may occur during treatment and take this into account while driving or using machines.


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4.8 Undesirable effects

The estimation of the frequency of undesirable effects is based on a pooled analysis of data from clinical trials and spontaneous reporting.

Based on pooled data from clinical trials including more than 250 patients who received bendroflumethiazide, approximately 12% of patients can be expected to experience an undesirable effect.

The most frequently reported adverse reactions during treatment are dizziness (including orthostatic hypotension and vertigo) and headache both occurring in approximately 5% of patients and fatigue occurring in approximately 4% of patients. Hypokalemia and electrolyte disturbances can occur especially during long-term treatment.

Renal failure has been reported in post-marketing safety surveillance.

Undesirable effects are listed by MedDRA SOC and the individual undesirable effects are listed starting with the most frequently reported. Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Very common ≥1/10

Common ≥1/100 and <1/10

Uncommon ≥1/1,000 and <1/100

Rare ≥1/10,000 and <1/1,000

Very rare <1/10,000

Endocrine disorders

Uncommon:

(≥1/1,000 and <1/100)

Hyperparathyroidism

Metabolism and nutrition disorders

Common:

(≥1/100 and <1/10)

Hypokalaemia

Hyperuricaemia and gout

Uncommon:

(≥1/1,000 and <1/100)

Diabetes mellitus

Acid base balance abnormal

Dehydration

Hypochloraemia

Hyponatraemia

Hypocalcaemia

Hypomagnesaemia

Weight increased

Nervous system disorders

Common:

(≥1/100 and <1/10)

Dizziness (including orthostatic hypotension and vertigo)

Headache

Fatigue

Uncommon:

(≥1/1,000 and <1/100)

Syncope

Ataxia

Paraesthesia

Dysgeusia

Psychiatric disorders

Uncommon:

(≥1/1,000 and <1/100)

Depression

Confusional state

Sleep disorder

Eye disorders

Uncommon:

(≥1/1,000 and <1/100)

Eye disorder and vision blurred

Cardiac disorders

Uncommon:

(≥1/1,000 and <1/100)

Palpitations and cardiovascular disturbance

Vascular disorders

Uncommon:

(≥1/1,000 and <1/100)

Hypotension

Flushing

Peripheral coldness

Respiratory, thoracic and mediastinal disorders

Uncommon:

(≥1/1,000 and 1/100)

Respiratory disorder

Dyspnoea and wheezing

Gastrointestinal disorders

Common:

(≥1/100 and <1/10)

Gastrointestinal disturbances

Nausea

Dry mouth and thirst

Uncommon:

(≥1/1,000 and 1/100)

Diarrhoea

Vomiting

Constipation

Abdominal pain and discomfort

Skin and subcutaneous tissue disorders

Common:

(≥1/100 and <1/10)

Skin disorder (including rash, urticaria and eczema)

Uncommon:

(≥1/1,000 and 1/100)

Photosensitivity reaction

Pruritus

Hyperhidrosis

Musculoskeletal and connective tissue disorders

Common:

(≥1/100 and <1/10)

Pain (including arthralgia and myalgia)

Uncommon:

(≥1/1,000 and 1/100)

Muscle spasms and twitching

Renal and urinary disorders

Uncommon:

(≥1/1,000 and 1/100)

Renal impairment (including renal failure)

Creatinine urine increased

Polyuria and nocturia

Reproductive system and breast disorders

Uncommon:

(≥1/1,000 and 1/100)

Erectile dysfunction

General disorders and administration site conditions

Common:

(≥1/100 and <1/10)

Influenza like symptoms (including cough and rhinitis)

Uncommon:

(≥1/1,000 and 1/100)

Oedema (including peripheral oedema and face oedema)

Blood dyscrasias including thrombocytopenia, leucopenia and granulocytopenia have been observed as class effects for thiazides.

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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971;

Fax: +353 1 6762517. Website: http://www.hpra.ie/; E-mail: medsafety@hpra.ie.


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4.9 Overdose

In high doses, thiazide diuretics may cause electrolyte imbalance, dehydration and polyuria.

Symptoms of electrolyte imbalance include dry mouth, thirst, weakness, lethargy, drowsiness, gastrointestinal disturbances, restlessness, muscle pain and cramps, and seizures.

Treatment is adjustment of the fluid and electrolyte imbalance.

In addition, high doses of potassium may cause hyperkalaemia symptoms and effects on the heart such as hypotension, bradycardia, heart block and cardiac arrhythmia. Respiratory depression and gastric symptoms due to erosion and acidosis may develop.


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5. PHARMACOLOGICAL PROPERTIES

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5.1 Pharmacodynamic properties

ATC code: C03A B01

Low Centyl® K is a combination of a thiazide diuretic with a potassium supplement. Bendroflumethiazide acts on both determinants of hypertension i.e. cardiac output and peripheral resistance.

Cardiac output is reduced due to a decrease in blood volume resulting from the diuretic effect. Peripheral resistance is reduced by a vasodilating effect, the mechanism of which is not completely understood. In oedematous conditions, the diuretic action reduces extravascular fluid volume.

Some degree of potassium depletion may be associated with prolonged thiazide therapy. A potassium supplement is therefore included in Low Centyl® K to help counteract this. Because of the reported dangers of localised high concentrations of potassium salts in the small bowel, the potassium chloride in Low Centyl® K is formulated in an inert wax core from which it is gradually released over several hours. The bendroflumethiazide is contained in a coat which surrounds the central core.


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5.2 Pharmacokinetic properties

Bendroflumethiazide is well absorbed from the gastrointestinal tract after oral administration and the absorption is not affected by food. Plasma protein binding, as with most thiazides, is high. The plasma half-life averaged 3.9 hours after a 5 mg dose. There is evidence that bendroflumethiazide is fairly extensively metabolised; about 30% is excreted unchanged in the urine.


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5.3 Preclinical safety data

No additional data.


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6. PHARMACEUTICAL PARTICULARS

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6.1 List of excipient(s)

Core:

ethyl cellulose

glycerol

stearyl alcohol

magnesium stearate

Film Coating:

glycerol

hypromellose 15 cps

hypromellose 3 cps

citric acid monohydrate

saccharin sodium

talc

titanium dioxide (E171)

polysorbate 20

quinoline yellow lake (E104)


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6.2 Incompatibilities

Not applicable.


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6.3 Shelf life

3 Years.


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6.4 Special precautions for storage

Do not store above 30°C.

Keep the bottle tightly closed as the product is sensitive to moisture.


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6.5 Nature and contents of container

Amber glass bottles with polypropylene screw cap and a desiccant (silica) containing 25, 30, 100 or 250 modified-release tablets.

Or

High-density polypropylene (HDPE) bottle with a polypropylene (PP) tamper-evident closure with an integrated silica gel desiccant. Pack sizes of 25, 30, 100 or 250 modified-release tablets.

Not all pack sizes may be marketed.


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6.6 Special precautions for disposal and other handling

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


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7. MARKETING AUTHORISATION HOLDER

LEO Laboratories Limited, Cashel Road, Dublin 12.


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8. MARKETING AUTHORISATION NUMBER(S)

PA 46/19/2


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9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 14 November 1997

Date of last renewal: 14 November 2007


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10. DATE OF REVISION OF THE TEXT

October 2014


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LEGAL CATEGORY

Product subject to prescription which may be renewed.



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Active Ingredients

 
   Potassium Chloride
   Bendroflumethiazide