Annin Co Tablet

ANNIN CO is indicated for the treatment of hypertension in patients established on identical doses of the individual medicines.

The maximum dose is one tablet of ANNIN CO (100 mg losartan potassium and 25 mg hydrochlorothiazide) once daily. The maximum antihypertensive effect is attained within three weeks after initiation of therapy. ANNIN CO should not be initiated in patients who are intravascularly volume depleted (e.g. those treated with high dose of diuretics). ANNIN CO is not recommended for patients with severe renal impairment or for patients with hepatic impairment (see also section 4.4) ANNIN CO should not be used as initial therapy in elderly patients. ANNIN CO may be administered with other antihypertensive medicines, such as calcium channel blockers and beta-blockers. ANNIN CO may be administered with or without food.

Special Populations

Renally and Hepatically Impaired Patients
ANNIN CO is not recommended for patients with severe renal impairment or for patients with hepatic impairment (see also section 4.3 and 4.4)

Elderly
A higher dose (100 mg losartan potassium and 25 mg hydrochlorothiazide should not be used as initial therapy in elderly patients.

Method of administration
ANNIN CO is administered orally, with or without food.

ANNIN CO is contraindicated in:

• Hypersensitivity to losartan or hydrochlorothiazide or any of the components of ANNIN CO (see section 6.1).
• A history of angioedema related to previous therapy with Angiotensin Converting Enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs): These patients must never again be given these medicines.
• Hereditary or idiopathic angioedema.
• Hypertrophic obstructive cardiomyopathy (HOCM).
• Severe renal function impairment (creatinine clearance less than 30 mL/min).
• Bilateral renal artery stenosis.
• Renal artery stenosis in patients with a single kidney.
• Aortic stenosis.
• Concomitant therapy with potassium sparing diuretics such as spironolactone, triamterene, amiloride (see also section 4.5).
• Porphyria.
• Thiazide diuretics in (fixed dose) combination with ANNIN CO should not be given to patients with Addison's disease.
• This therapy is also contraindicated in patients with severe renal impairment or is also contraindicated in patients with anuria, and hypersensitivity to other sulphonamide-derived medicines.
• Lithium therapy: Concomitant administration with ANNIN CO may lead to toxic blood concentrations of lithium.
• Pregnancy and lactation (see also section 4.6).
• Hepatic impairment.
• The concomitant use of ANNIN CO with aliskiren-containing products is contraindicated (see also section 4.4 and 4.5).
• The concomitant use of fluoroquinolones with ACE inhibitors/Renin-Angiotensin blockers is contraindicated in patients with moderate to severe renal impairment.
• Patients with a history or previous and/or current basal cell carcinomas and/or squamous cell carcinomas of the skin and lip.

Paediatric Use: Safety and efficacy in children has not been established.

Pregnancy
Should a woman become pregnant while receiving ANNIN CO, the treatment should be stopped immediately and if appropriate, alternative therapy should be started. (see section 4.6).

Hypersensitivity: Angioedema - patients with a history of angioedema (swelling of the face, lips, throat, and/or tongue) should be closely monitored.

Hepatic and renal impairment
ANNIN CO is not recommended for patients with hepatic impairment or severe renal impairment (see section 4.2 and 4.3). As a consequence of inhibiting the renin-angiotensin system, changes in renal function including renal failure have been reported. These changes in renal function may not be reversible upon discontinuation of therapy. ANNIN CO may increase blood urea and serum creatinine in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney (see also section 4.3).

Hypotension and electrolyte/fluid imbalance
In patients who are intravascularly volume-depleted (e.g. those treated with high-dose diuretics), symptomatic hypotension may occur, especially after the first dose. These conditions should be corrected prior to administration of ANNIN CO or a lower starting dose should be used (see also section 4.2). Periodic determination of serum electrolytes should be performed at appropriate intervals.

Metabolic and endocrine effects
Thiazide therapy may impair glucose tolerance. Dosage adjustment of antidiabetic medicines, including insulin, may be required (see also section 4.5). Hydrochlorothiazide as in ANNIN CO may decrease urinary calcium excretion and may cause an elevation of serum calcium. Marked hypercalcaemia may be evidence of occult hyperparathyroidism. ANNIN CO should be discontinued before carrying out tests for parathyroid function. Increases in cholesterol and triglyceride levels may be associated with hydrochlorothiazide therapy. ANNIN CO may precipitate hyperuricaemia and/or gout in certain patients.

Renal transplantation
There is no experience in patients with recent kidney transplantation.

Primary hyperaldosteronism
Patients with primary aldosteronism generally will not respond to antihypertensive drugs acting through inhibition of the renin-angiotensin system. Therefore, the use of ANNIN CO is not recommended.

Coronary heart disease and cerebrovascular disease
As with any antihypertensive agents, excessive blood pressure decrease in patients with ischaemic cardiovascular and cerebrovascular disease could result in a myocardial infarction or stroke.

Heart failure
In patients with heart failure, with or without renal impairment, there is - as with other drugs acting on the renin-angiotensin system - a risk of severe arterial hypotension, and (often acute) renal impairment.

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy
As with other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy.

Non-melanoma skin cancer
An increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] with increasing cumulative dose of hydrochlorothiazide exposure has been observed in two epidemiological studies based on the Danish National Cancer Registry. Photosensitizing actions of hydrochlorothiazide could act as a possible mechanism for NMSC. Patients taking hydrochlorothiazide should be informed of the risk of NMSC and advised to regularly check their skin for any new lesions and promptly report any suspicious skin lesions. Possible preventive measures such as limited exposure to sunlight and UV rays and, in case of exposure, adequate protection should be advised to the patients in order to minimize the risk of skin cancer. Suspicious skin lesions should be promptly examined potentially including histological examinations of biopsies. The use of hydrochlorothiazide may also need to be reconsidered in patients who have experienced previous NMSC (see also section 4.8).

Concomitant use with Lithium
Concomitant administration of lithium with ANNIN CO may lead to toxic blood concentrations of lithium (see also section 4.3).

Other
In patients receiving hydrochlorothiazide as in ANNIN CO hypersensitivity reactions may occur with or without a history of allergy or bronchial asthma. Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazides.

Dual blockade of renin-angiotensin-aldosterone system (RAAS)
There is evidence that the concomitant use of ACE inhibitors, ARBs or aliskiren may increase the risk of hypotension hyperkalaemia and decrease renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ANNIN CO and aliskiren is therefore not recommended. ANNIN CO should not be used concomitantly with aliskiren (see also section 4.3).

Concomitant use of fluoroquinolones and ACE inhibitors/renin-angiotensin receptor blockers
may precipitate acute kidney injury inpatients, especially those with moderate to severe renal impairment and elderly patients (see section 4.3). Renal function should be assessed before initiating treatment and monitored during treatment, with fluoroquinolones or ACE inhibitors/renin-angiotensin receptor blockers.

Excipient
ANNIN CO contains lactose. Patients with rare hereditary problems of galactose intolerance e.g. galactosaemia, the Lapp lactase deficiency or glucose-galactose malabsorption should not take ANNIN CO.

Paediatric Use
Safety and efficacy in children has not been established.

INTERACTIONS

Losartan potassium
In clinical pharmacokinetic trials, no interactions of clinical significance have been identified with hydrochlorothiazide, digoxin, warfarin, cimetidine, phenobarbitone (see Hydrochlorothiazide, Alcohol, barbiturates or narcotics below) ketoconazole and erythromycin. Rifampin and fluconazole have been reported to reduce levels of the active metabolite. The clinical consequences of these interactions have not been evaluated.

Concomitant use of fluoroquinolones and ACE inhibitors/renin angiotensin receptor blockers may precipitate acute kidney injury (see section 4.3).

Concomitant use of medicines that block angiotensin II or its effects and potassium-sparing diuretics (e.g. spironolactone, triamterene, amiloride), potassium supplements or salt substitutes containing potassium may lead to increases in serum potassium. Lithium excretion may be reduced. Therefore, concomitant administration of lithium and ANNIN CO is contraindicated (see section 4.3).

Hydrochlorothiazide
When administered concurrently the following medication may interact with thiazide diuretics: Alcohol, barbiturates or narcotics: Potentiation of orthostatic hypotension may occur. Antidiabetic medicines (oral medicines and insulin): Dosage adjustment of the antidiabetic medicine may be required. Other antihypertensive medicines: Additive effect or potentiation. Cholestyramine and colestipol resins: Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85 and 43 % respectively. ANNIN CO should therefore be administered one hour before the intake of the resin. Corticosteroids, ACTH or glycyrrhizin (found in liquorice): Intensified electrolyte depletion, particularly hypokalaemia. Pressor amines (e.g. norepinephrine): Possible decreased response to pressor amines but not sufficient to preclude their use. Skeletal muscle relaxants, non-depolarising (e.g. tubocurarine): Possible increased responsiveness to the muscle relaxant. Lithium: Diuretic medicines reduce the renal clearance of lithium and add a high risk of lithium toxicity. Therefore, the concomitant use of lithium and ANNIN CO is contraindicated (see section 4.3). Non-steroidal anti-inflammatory drugs (NSAIDs) including cyclooxygenase-2 Inhibitors: The administration of a non-steroidal anti-inflammatory medicine including a selective cyclooxygenase - 2 inhibitor can reduce the diuretic, natriuretic and antihypertensive effects of ANNIN CO. Paediatric Use: Safety and efficacy in children has not been established.

Pregnancy
Safety in pregnancy and lactation has not been established (see also section 4.3). The use of ANNIN CO is contra-indicated during pregnancy. Pregnant women should be informed of the potential hazards to the foetus and must not take ANNIN CO during pregnancy. Patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is detected or suspected ANNIN CO should be discontinued as soon as possible. ANNIN CO should not be used in pregnancy as teratogenicity has been shown in experimental animals.

Lactation
Safety in breastfeeding has not been established (see section 4.3). Thiazides appear in human milk.

There is no data to suggest that ANNIN CO affects the ability to drive and use machines. However, when driving vehicles or operating machinery it must be borne in mind that dizziness or drowsiness may occasionally occur when taking antihypertensive therapy, in particular during initiation of treatment or when the dose is increased.

a. Tabulated list of adverse reactions

The adverse reactions below are classified where appropriate by system organ class.

SYSTEM ORGAN CLASS ADVERSE REACTION FREQUENCY

Nervous system disorders Dizziness Frequent

General disorders and administration site conditions Asthenia/fatigue. Frequent

Losartan potassium

SYSTEM ORGAN CLASS ADVERSE REACTION FREQUENCY

Psychiatric disorders Insomnia Frequent

Nervous system disorders Headache, dizziness Frequent

Cardiac disorders Palpitation, tachycardia Frequent

Vascular disorders Orthostatic hypotension Less frequent

Respiratory, thoracic and mediastinal disorders Cough, pharyngitis, nasal congestion, sinus disorder, upper respiratory infection Frequent:

Gastrointestinal disorder Diarrhoea, nausea, abdominal pain, dyspepsia Frequent

Skin and subcutaneous tissue disorders Rash Less Frequent

Musculoskeletal, connective tissue and bone disorders Back pain, muscle cramps Frequent

General disorders and administration site conditions Asthenia/fatigue, oedema/swelling, chest pain Frequent

Investigations Hyperkalaemia, elevations of ALT Frequent

Hydrochlorothiazide

SYSTEM ORGAN CLASS ADVERSE REACTION FREQUENCY

Blood and the lymphatic system disorders Thrombocytopenia, leukopenia, agranulocytosis, haemolytic anaemia Less frequent:

Metabolic and nutrition disorders Anorexia, hyperuricaemia, hyperglycaemia Less frequent

Nervous system disorders Paraesthesia, headache Less frequent

Vascular disorders Hypotension (including orthostatic hypotension) Less frequent

Respiratory, thoracic and mediastinal disorders Respiratory distress including pneumonitis and pulmonary oedema Less frequent

Gastrointestinal disorder Nausea, vomiting, diarrhoea, constipation, pancreatitis Less frequent

Hepatobiliary disorders Jaundice (intrahepatic cholestatic jaundice) Less frequent

Skin and subcutaneous tissue disorders Rash, urticaria, photosensitivity. necrotising angitis (vasculitis and cutaneous vasculitis) Less Frequent

Renal and urinary disorders Glycosuria Less frequent

Post-marketing data

The following adverse reactions have been reported in post-marketing experience; they are derived from spontaneous reports for which precise incidences cannot be determined therefore, the frequency is unknown:

SYSTEM ORGAN CLASS ADVERSE REACTION

Blood and the lymphatic system disorders Aplastic anaemia, thrombocytopenia

Immune system disorders Anaphylactic reactions, angioedema including swelling of the larynx and glottis, causing airway obstruction and/or swelling of the face, lips, pharynx and/or tongue has been reported rarely in patients treated with losartan; some of these patients previously experienced angioedema with other medicine including ACE inhibitors

Metabolic and nutrition disorders Electrolyte imbalance including hyponatraemia and hypokalaemia

Psychiatric disorders Restlessness

Nervous system disorders Dysgeusia (reported with losartan)

Eye disorders Xanthopsia, transient blurred vision

Ear and labyrinth disorders Vertigo

Vascular disorders Hypotension, vasculitis, including Henoch-Schoenlein purpura

Respiratory, thoracic and mediastinal disorders Cough

Gastrointestinal disorder Gastric irritation, sialoadenitis, diarrhoea, vomiting

Hepatobiliary disorders Hepatitis

Skin and subcutaneous tissue disorders Purpura (including Henoch-Schoenlein purpura), pruritus, toxic epidermal necrolysis, cutaneous lupus erythematosus, urticaria, erythroderma has been reported with losartan, photosensitivity

Musculoskeletal, connective tissue and bone disorders Cramping, muscle spasm, myalgia, arthralgia (reported with losartan)

Renal and urinary disorders Renal dysfunction, interstitial nephritis, renal failure

General disorders and administration site conditions Fever, weakness, malaise

Investigations Liver function abnormalities.

Limited data are available in regard to overdosage in humans. The most likely manifestation of overdosage would be hypotension and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be instituted. Neither losartan nor the active metabolite can be removed by haemodialysis.

Hydrochlorothiazide
The most common signs and symptoms observed are those caused by electrolyte depletion (hypokalaemia, hypokalaemia, hyponatraemia) and dehydration resulting from excessive diuresis. If digoxin has also been administered, hypokalaemia may accentuate cardiac dysrhythmias. The degree to which hydrochlorothiazide is removed by haemodialysis has not been established.