Co-Triamterzide Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Co- Triamterzide Tablets BP
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains Hydrochlorothiazide 25 mg and Triamterene 50 mg. For excipients. see 6.1.
3. PHARMACEUTICAL FORM
Tablet.
A peach coloured, flat bevelled edged tablet, with a breakline on one side, the other side embossed with the Co-pharma logo (mortar and pestle).
4. CLINICAL PARTICULARS
4.1. Therapeutic Indications
Co-triamterzide tablets are recommended for the treatment of mild to moderate hypertension (alone or in combination with other anti-hypertensive drugs).
They are also used in the control of oedema in cardiac failure, cirrhosis of the liver or the nephrotic syndrome and in that associated with corticosteroid treatment.
4.2. Posology and Method of Administration
Adults only:
In hypertension: Initially one tablet a day after the morning meal, thereafter adjusted to the patient’s needs. If Co-triamterzide tablets are added to already established therapy with another antihypertensive, then the dosage of the latter should be reduced and adjusted later if necessary. If another antihypertensive drug is added to Co-triamterzide tablet therapy, the dosage of the latter will not normally be reduced.
In oedema: The usual starting dosage is one Co-triamterzide tablet twice a day after meals. The optimal dosage may be three tablets a day, two after breakfast and one after lunch. Once diuresis has been established a maintenance dose of usually one tablet a day, or two tablets on alternate days should be instituted.
A dosage of four tablets a day should not be exceeded as adverse reactions such as raised blood urea are more likely to occur.
Use in the elderly:
Dosage as above. Co-triamterzide tablets have been widely used and are usually well tolerated, however the normally occurring reduction in glomerular filtration rate with age should be borne in mind.
Use in children:
Only limited information is available on the use of Co-Triamterzide in children and therefore its use in children is not recommended.
4.3 Contra-Indications
Co-triamterzide tablets must not be given to patients with hyperkalaemia, progressive renal failure, increasing hepatic dysfunction, hypercalcaemia, diabetic ketoacidosis, Addison’s disease or known hypersensitivity to either hydrochlorothiazide or triamterene, to other sulphonamide derived drugs. or to any of the excipients. Potassium supplements, or other potassium-conserving drugs, including ACE inhibitors, should not be given routinely with Co-triamterzide tablets.
4.4 Special warnings and precautions for use
It is advisable to monitor electrolytes, blood urea and serum potassium levels periodically. This is especially important in the elderly, those with renal impairment and those receiving concomitant treatment with NSAIDs (see section 4.5).
Hyperkalaemia
Hyperkalaemia may occur in patients taking potassium sparing diuretics, especially in the elderly or hospitalised patients with hepatic cirrhosis or congestive heart failure with renal involvement, in seriously ill patients or in those undergoing vigorous diuretic treatment. Uncorrected hyperkalaemia may be fatal, therefore such patients should be carefully observed for clinical, laboratory and ECG evidence of hyperkalaemia.
As ECG changes may not be present, it is important to monitor serum potassium levels. Potassium supplements and potassium-rich foods should be avoided, except in cases of severe or refractory hypokalaemia where careful monitoring of serum potassium levels is required (see section 4.3).
If hyperkalaemia does develop, co-triamterzide treatment should be discontinued immediately and active measures taken to reduce plasma potassium to normal levels.
Electrolyte imbalance
Patients should be monitored for fluid and electrolyte imbalance, hyponatraemia, hypochloraemic alkalosis, hypokalaemia and hypomagnesaemia. It is particularly important to make serum and urine electrolyte determinations when the patient is vomiting excessively or receiving parenteral fluids. Warning signs or symptoms of fluid or electrolyte imbalance include: dryness of the mouth, weakness, lethargy, drowsiness, restlessness, seizures, confusion, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastro-intestinal disturbances such as nausea and vomiting.
Hypokalaemia may develop due to aggressive diuretic therapy, after prolonged therapy or if there is severe liver cirrhosis. This may sensitise or exaggerate the heart’s response to digitalis toxicity (see section 4.5).
Diuretic-induced hyponatraemia is usually mild and asymptomatic, although it may become severe and symptomatic. If this occurs, the patient requires prompt treatment.
Impaired renal function
Renal function should be monitored because the use of co-triamterzide in impaired renal function may result in the rapid development of hyperkalaemia. Thiazide diuretics are ineffective when creatinine clearance falls below 30 ml/min.
Uraemia may be precipitated or increased by hydrochlorothiazide. In patients with impaired renal function, cumulative effects may be seen. Co-triamterzide should be discontinued if increasing uraemia and oliguria develop.
Hepatic dysfunction
Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease (see section 4.3). Minor alteration of electrolyte and fluid balance may precipitate hepatic coma.
The use of folate antagonists and triamterene are inadvisable in patients with hepatic cirrhosis because of the theoretical risk of increased folate deficiency.
Metabolic effects
Hyperuricaemia may occur, or gout may be aggravated or precipitated in certain patients. Hypersensitivity reactions to allopurinol have been reported to occur more frequently in patients receiving thiazide diuretics (see section 4.5).
Thiazides may impair glucose tolerance. Diabetes mellitus may be precipitated or aggravated by co-triamterzide therapy. Dosage adjustment of antidiabetic agents may be required (see section 4.5).
To minimise the risk of hyperkalaemia in diabetic patients and in diabetic nephropathy, the renal function should be assessed before co-triamterzide therapy. Co-triamterzide should be discontinued for at least 3 days before a glucose tolerance test.
Potassium-sparing treatment should be started with caution in severely ill patients, where metabolic or respiratory acidosis may occur (such as cardiopulmonary disease or inadequately controlled diabetes). Shifts in acid base balance alter the balance of potassium in and outside the cells; the development of acidosis may be associated with a rapid increase in plasma potassium.
Increases in plasma cholesterol and triglyceride levels may be seen.
Lithium
Triamterene and thiazides reduce the excretion of lithium and may precipitate lithium toxicity.
Systemic lupus erythematosus
Thiazides may activate or exacerbate systemic lupus erythematosus.
Pancreatitis
Pancreatitis may be aggravated.
Interference with laboratory tests
Thiazides may decrease urinary calcium excretion, or may cause intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Co-triamterzide may interfere with some laboratory tests of thyroid and parathyroid function. Triamterene interferes with bioassays of folic acid. Co-triamterzide therapy should be discontinued before such tests are performed.
Triamterene may cause blue fluorescence of urine under certain light conditions.
Excipients
Co-triamterzide contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Co-triamterzide contains Sunset yellow (E110) which can cause allergic reactions including asthma. Allergy is more common in those people who are allergic to aspirin.
4.5 Interaction with other medicinal products and other forms of interaction
Interactions affecting the use of co-triamterzide NSAIDs
There have been reports of renal failure, reversible on stopping treatment, in patients receiving triamterene and some NSAIDs. Concomitant administration of indometacin and triamterene may result in decreased renal function; concomitant use should be avoided. NSAIDs may attenuate the diuretic and antihypertensive effects of thiazide diuretics. Concomitant administration of NSAIDs and potassium sparing diuretics may cause hyperkalaemia and renal failure, particularly in the elderly. Therefore when co-triamterzide is used concurrently with NSAIDs, renal function and serum potassium should be carefully monitored.
Anion exchange resins
Single doses of either colestyramine or colestipol resins reduce the absorption of hydrochlorothiazide from the gastrointestinal tract by up to 85 and 43 percent respectively. When colestyramine is given 4 hours after the hydrochlorothiazide, the absorption of hydrochlorothiazide is reduced by 30 to 35 percent.
Antidepressants: When co-administered with reboxetine there is an increased risk of hypokalaemia. There is an increased risk of postural hypotension with tricyclics. An enhanced hypotensive effect may also occur when given in conjunction with MAOIs.
Corticosteroids,
Corticosteroids and other similar medications may antagonise the diuretic action of co-triamterzide.
CNS depressant agents
Co-administration of alcohol, barbiturates or narcotics may potentiate orthostatic hypotension.
Interactions affecting the use of other medications Lithium
Triamterene and thiazides reduce excretion of lithium and may thus precipitate lithium toxicity.
Antihypertensive agents
Close supervision and observation is recommended after the first dose of an angiotensin converting enzyme (ACE) inhibitor or angiotensin II receptor antagonist due to the risk of first dose hypotension. Consideration should be given to reducing the dose or temporarily withdrawing treatment, two to three days before an ACE inhibitor is introduced. There is an increased risk of hyperkalaemia when potassiumsparing diuretics are administered with ACE inhibitors or angiotensin II receptor antagonists.
The dose of concurrently administered antihypertensives (especially alpha-adrenergic blockers) or other drugs with blood pressure lowering potential may require adjustment when co-triamterzide is added to existing therapy as additive hypotensive effects may occur.
Medications affected by electrolyte disturbances
Consideration should be given to the possibility of electrolyte disturbances when co-triamterzide is administered concurrently with other drugs that also have this effect. Appropriate monitoring is recommended (section 4.4). Electrolyte disturbances such as hypokalaemia may increase the toxicity and the risk of arrythmias associated with certain drugs (e.g. cardiac glycosides, amisulpride, atomoxetine, pimozide, sotalol, sertindole, thioridazine).
There is increased risk of hypokalaemia with concurrent use of thiazide diuretics and corticosteroids, ACTH, theophylline, amphotericin, reboxetine or loop diuretics.
Sympathomimetics
There is an increased risk of hypokalaemia if thiazides are taken with high doses of bambuterol, fenoterol, eformoterol, ritodrine, salbutamol, salmeterol and terbutaline. Monitoring of serum potassium is recommended .
Increased risk of hyperkalaemia occurs when triamterene is taken with potassium salts or drugs which reduce potassium excretion or elevate serum potassium levels, e.g. ACE inhibitors, angiotensin II receptor antagonists, NSAIDs, aliskiren, ciclosporin, drospirenone, tacrolimus, trilostane.
There is an increased risk of hypercalcaemia, if thiazide diuretics are administered with vitamin D, calcium salts or toremifene. Metabolic alkalosis and renal failure can occur if high doses of vitamin D and/or large amounts of calcium are given with thiazides.
Concomitant use with carbamazepine may increase the risk of hyponatraemia.
Neuromuscular blocking agents
Non-depolarising muscle relaxants may possibly interact with co-triamterzide to cause increased muscle relaxation.
Allopurinol
Thiazide diuretics may cause predisposition to allopurinol hypersensitivity reactions.
Fluconazole
Hydrochlorothiazide increases plasma levels of fluconazole. Although no dose adjustment of fluconazole is generally required the prescriber should be aware of this interaction.
Anti-diabetic agents
Co-triamterzide may antagonise the effects of oral and parenteral hypoglycaemic agents and dose adjustment may be required. Chlorpropamide increases the risk of hyponatraemia associated with thiazides in combination with potassium-sparing diuretics.
Interactions
• Ulcer healing drugs such as carbenoxolone antagonises the diuretic effect. Concurrent administration with thiazides increases the risk of hypokalaemia.
• Cytotoxics: Increased risk of nephrotoxicity and ototoxicity has been reported with platinum compounds like cisplatin.
• Muscle Relaxants: Enhanced hypotensive effect with baclofen and tizanidine.
• Oestrogens and progestogens: Oestrogens and combined oral contraceptives antagonise diuretic effect e.g. Drospirenone. Possible hyperkalaemia may occur with potassium sparing diuretics.
4.6 Pregnancy and lactation
Pregnancy
Diuretic use in pregnant women may be associated with hypovolaemia, increased blood viscosity, or decreased placental perfusion. Diuretics do not prevent preeclampsia developing and there is no satisfactory evidence of their usefulness.
There are no adequate and well-controlled studies in pregnant women, therefore Co-triamterzide should not be used in pregnancy unless it is considered that the benefits to the mother outweigh the risks to the foetus.
The combined use of folate antagonists and triamterene during pregnancy has an increased theoretical risk of folate deficiency and is not advised.
Thiazides and triamterene cross the placental barrier and are detectable in cord blood. The possible risks to the foetus or newborn include jaundice, hypoglycaemia, pancreatitis, thrombocytopenia and bone marrow depression.
Lactation
Thiazides are detectable in human breast milk; triamterene appears in animal milk and this may also occur in humans. If use of Co-triamterzide is considered essential, the mother should stop breast-feeding. Thiazides in high doses causing intense diuresis can inhibit the milk production.
4.7. Effects on Ability to Drive and Use Machines
No or negligible effect, except dizziness, weakness and headache are listed as side-effects of Co-triamterzide tablets. The patient should be cautioned not to drive or operate machinery should any of these effects occur.
4.8 Undesirable effects
The following undesirable effects have been reported with Co-triamterine or either of the individual components. Frequency for the combination cannot be estimated from the available data.
Co-triamterizide
Gastrointestinal disorders: nausea, vomiting, dry mouth, acute pancreatitis, diarrhoea
Musculoskeletal and Connective tissue disorders: muscle cramps,
General disorders and administration site conditions: weakness, thirst
Cardiac disorders: undesirable decrease in blood pressure
Investigations: Minor serum electrolyte changes have been observed infrequently, and marked fluctuations in serum potassium levels are uncommon. Long-term use has confirmed that little change occurs in serum potassium and sodium levels in most patients. Metabolic acidosis occasionally occurs. Electrolyte imbalance may also indicate excessive dosage or be secondary to the condition under treatment. Increased uric acid levels which sometimes lead to gout, and hypercalcaemia that does not lead to tertiary hyperparathyroidism may also occur. Co-triamterzide may reduce glomerular filtration rate and cause a temporary increase in blood urea and creatinine levels; again this may also indicate excessive dosage or be secondary to the condition under treatment: it can also cause increases in plasma lipid levels
Skin and subcutaneous tissue disorders: rash, photosensitivity,
Immune system disorders: systemic lupus erythematosus, anaphylaxis
Metabolism and nutrition disorders: metabolic acidosis, gout
Endocrine disorders: hyperglycaemia
Renal and urinary disorders: renal failure due to acute interstitial nephritis. Triamterene has been found in renal stones both alone and in association with other usual calculus components. There is no evidence that stone formation is increased in patients taking triamterene containing drugs.
Blood and lymphatic system disorders: thrombocytopenic purpura, megaloblastic anaemia, jaundice, blood dyscasias including agranulocytosis, thrombocytopenia, leucopenia
Respiratory, thoracic and mediastinal disorders: acute interstitial pneumonitis, pulmonary oedema
Nervous system disorders: headache, dizziness Hydrochlorothiazide
Blood and lymphatic system disorders: Agranulocytosis, aplastic anaemia, haemolytic anaemia, leucopenia, thrombocytopenia, thrombocytopenic purpura
Immune system disorders: Anaphylaxis, vasculitis, urticaria, cutaneous vasculitis
Metabolism and nutrition disorders: Glycosuria,
Nervous system disorders: Restlessness
Eye disorders: Transient blurred vision, xanthopsia
Endocrine disorders: hyperglycaemia
Vascular Disorders: vasculitis necrotising
Respiratory, thoracic and mediastinal disorders: Respiratory distress, pneumonitis, pulmonary oedema
Gastrointestinal disorders: Stomach discomfort, pancreatitis Infections and infestations: sialoadenitis Hepatobiliary disorders: Cholestatic jaundice
Skin and subcutaneous tissue disorders: photosensitivity, toxic epidermal necrolysis Renal and urinary disorders: Interstitial nephritis,
General disorders and administration site conditions: Pyrexia
The following undesirable effects have been reported with triamterene with their Frequency by their side.
Triamterene
|
Blood and lymphatic system disorders |
Rare or very rare (<1/1000, including case reports) |
megaloblastic anaemia, pancytopenia |
|
Metabolism and nutrition disorders |
Very common or common (>1/100) |
hyperkalaemia (incidence is reduced by Furosemide) |
|
Uncommon (>1/1,000, <1/100) |
hyperuricaemia | |
|
Nervous system disorders |
Uncommon (>1/1,000, <1/100) |
Headache |
|
Vascular disorders |
Uncommon (>1/1,000, <1/100) |
hypovolaemia |
|
Gastrointestinal disorders |
Very common or common (>1/100) |
nausea, vomiting, diarrhoea |
|
Uncommon (>1/1,000, <1/100) |
dry mouth | |
|
Skin and subcutaneous tissue disorders |
Uncommon (>1/1,000, <1/100) |
Rashes |
|
Rare or very rare (<1/1000, including case reports) |
photosensitivity reactions, pseudoporphyria | |
|
Renal and urinary disorders |
Uncommon (>1/1,000, <1/100) |
elevation of s-creatinine, transient renal insufficiency |
|
Rare or very rare (<1/1000, including case reports) |
Interstitial nephritis, urinary stones | |
|
Injury poisoning and procedural complications |
Rare or very rare (<1/1000, including case reports) |
serum sickness |
Weakness, minor decreases in blood pressure, and rash have been reported. Anaphylaxis is a remote possibility.
Metabolic acidosis occasionally occurs. Electrolyte imbalance may also indicate excessive dosage or be secondary to the condition under treatment.
Renal failure, reversible on stopping treatment, has been reported very rarely and has been due to acute interstitial nephritis or an interaction between triamterene and some NSAIDs.
Triamterene has been found in renal stones both alone and in association with other usual calculus components. There is no evidence that stone formation is increased in patients taking triamterene containing drugs.
Jaundice and abnormalities of serum levels of liver enzymes, have also been reported. Triamterene may cause a blue fluorescence of the urine under certain light conditions. Triamterene interferes with bioassay of folic acid.
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.
4.9. Overdose
Symptoms of electrolyte imbalance, especially hyperkalaemia, are likely. Symptoms include nausea, vomiting, weakness, lassitude, muscular weakness, hypotension and cardiac arrhythmias. Treatment consists of gastric lavage with careful monitoring of electrolytes and fluid balance. Cardiac rhythm should be monitored and appropriate measures taken to correct hyperkalaemia as necessary. There is no specific antidote. Renal dialysis may be of some benefit in cases of severe overdosage.
5. PHARMACOLOGICAL PROPERTIES
5.1. Pharmacodynamic Properties
Pharmacodynamic properties
Low ceiling diuretics and potassium-sparing agents. C03E A01
Co-triamterzide tablets have an antihypertensive and diuretic action. The precise mechanism of action of the thiazide diuretics as anti-hypertensive agents is unknown, although the beneficial effects appear to result from an altered sodium balance. The dominant action of the thiazides as diuretics is to increase the renal excretion of sodium and chloride and accompanying volume of water. This effect is virtually independent of acid-base balance.
Triamterene has no significant pharmacological actions other than those on the kidneys and exerts its effect directly on the distal part of the distal tubule. Diuresis is characterised by an increase in the excretion of sodium, mostly accompanied by chloride as the anion, and under some circumstances by slight alkalinization of the urine. The combined effect of hydrochlorothiazide and triamterene on potassium excretion may be greatly modified by pharmacological means, and a sharp reduction in potassium output is then observed. Co-triamterzide tablets are rapidly absorbed from the gastrointestinal tract and show a demonstrable diuretic effect within an hour after oral administration.
5.2. Pharmacokinetic Properties
Following an oral dose, the bioavailability is approximately 70% for hydrochlorothiazide (HCTZ) and approximately 50% for triamterene. Peak plasma concentrations of both actives are achieved approximately 2-4 hours post-dosing and both are about 50% bound to plasma proteins. HCTZ accumulates in red blood cells, readily crosses the placenta and is only detected at very low levels in breast milk. Triamterene is probably excreted in breast milk and is likely to cross the placenta, but the extent is unknown. HCTZ is not metabolised in man and is excreted unchanged in the urine, whereas triamterene is excreted mainly as metabolites in the urine, following extensive metabolism.
5.3. Pre-clinical Safety Data
No data of relevance to the prescriber, which is additional to that included in other sections of the SPC.
6. PHARMACEUTICAL PARTICULARS
6.1. List of Excipients
Lactose
Modified cellulose gum (Ac-di-sol) Povidone K25
Dye Lennon Lake Yellow No.127 (E110) Alcohol 96%
Purified talc Magnesium stearate Microcrystalline cellulose
6.2. Incompatibilities
Not Applicable.
6.3. Shelf Life
4 years.
6.4. Special Precautions for Storage
Store below 25°C. Protect from light and moisture.
6.5. Nature and Content of Container
A1/PVC blisters containing 28, 30 and 50 tablets.
PP tablet container with LDPE or LDPE/HDPE snap-cap containing 30, 50, 100 and 500 tablets.
Not all pack sizes may be marketed.
6.6. Instructions for Use, Handling and Disposal
No special requirements.
7. MARKETING AUTHORISATION HOLDER
Strides Shasun (UK) Ltd Unit 4 Metro Centre Tolpits Lane Watford Hertfordshire WD18 9SS
Trading as: Co-pharma
8. MARKETING AUTHORISATION NUMBER
PL 13606/0096
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
24/04/2007
20/05/2016