Losazide

Losazide 

Losazide 

Losazide 

For the Medical Profession Only
Losazide
Film-coated Tablets
Use in pregnancy:
EIPICO
through the combined use of ACE-jnhibitors angiotensin Il receptor blockers or
aliskiren is therefore not recommended .
If dual blockade therapy is considered absolutely necessary, this should only occur
under specialist supervision and subject to frequent close monitoring of renal
function, electrolytes and blood pressure ACE-inhibitors and angiotensin Il receptor
blockers should not be used concomitantly in patients with diabetic nephropathy.
Angioedema: Patients with a history of angioedema (swelling of the face, lips,
throat, and/or tongue) should be closely monitored.
Hypotension and Intravascular volume depletion: Symptomatic hypotension,
especially after the first dose, may occur in patients who are volume-and/or
sodium-depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or
vomiting. Such conditions should be corrected before the administration of
Losazide tablets.
Electrolyte imbalances: ElectlOlyte imbalances are common in patients With renal
impairment, with or without diabetes, and should be. addressed. Therefore, the
plasma concentrations of potassium and creatinine clearance values should be
closely monitored; in particular patients with heart failure and a creatinine
clearance between 30-50 ml/ min should be closely monitored.
"Ille concomitant use of potassium sparing diuretics, potassium supplements and
potassium containing salt substitutes with Losazide is not recommended.
Liver function impairment: Based on pharmacokinetic data which demonstrate
significantly increased plasma concentrations of losartan in cirrhotic patients,
Losazide should be used with caution in patients with a history of mild to
moderate hepatic Impairment. There is no therapeutic experience with losartan in
patients with severe hepatic impairment. Therefore Losazide is contraindicated in
patients with severe hepatic impairment,
Renal -function impairment: As -a consequence of inhibiting the
renin-angiotensin-aldosterone system, changes in renal function, including renal
failure, have been reported (in particular, in patients whose renal function is
dependent on the renin-angfotensin-aldosterone system, such as those with severe
cardiac insufficiency or pre-existing renal dysfunction),
As with other drugs that affect the renin-angiotensin-aldosterone system, increases
in blood urea and serum creatinine have also been reported in patients with
bilateral renal artery stenosis orstenosis of the artery to a solitary kidney; these
changes in renal function may be reversible upon discontinuation of therapy
Losartan should be used with caution in patients with bilateral renal artery stenosis
or stenosisof the arteryX) a solitary kidney.
Renal transplantation: There is no experience in patients with recent kidney
transplantation.
Primary hyperaldosteronism: Patients With primary aldOsteronisrn generally will
not respond to antihypertensive drugs acting through inhibition of the renin-
angiotensin system. Therefore, the use of Losazide tablets is not recommended.
Coronary heart disease and cerebrovascular disease: As with any antihypertensive
agent, excessive blood presstne 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, o' obstructive hypertrophic cardiomyopathy.
Ethnic differences: As observed for angiotensin converting enzyrne inhibitors,
losartan and the other angiotensin antagonists are apparently less effective in
lowering blood pressure in black people than in non-blacks, possibly because of
higher prevalence of low-renin states in the black hypertensive population.
Hydrochlorothiazide:
Hypotension and electrolyte/fluid imbalance: As with all antihypertensive
therapy, symptomatic hypotension may occur in some patients. Patients should be
observed for clinical Signs of fluid or electrolyte imbalance, e.g. volume depletion,
hyponatraemia, hypochloraemic alkalosis, hypomagnesaemia or hypokalaemia
which may occur dunng intercurrent diarrhoea or vomiting. Periodic determination
of serum electrolytes should be performed at appropriate intervals in such patients.
Dilutional hyponattaemia may occur in oedematous patients in hot weather.
Metabolic and endocrine effects: Thiazide therapy may impair glucose tolerance.
Dosage adjustment of antidiabetic agents, including insulin, may be required.
Latent diabetes mellitus may become manifest during rhiande therapy.
Thiaudes may decrease urinary calcium excretion and may cause intermittent and
slight elevation of serurn calcium. Marked hypercalcaemia may be evidence of
hidden hyperparathyroidism. Thiazides should be discontinued before carrying
out testsfor parachyroid function.
Increases in cholesterol and trtglyceflde levels have been associated with thiazide
draretic therapy.
Thiazide therapy may hyperuricaemia and/or gout in certain patients.
Because losartan decreases uric acid. iosartan in cornbinatlon with hydrochlorothi-
azide attenuates the diuretic-induced hyperuricaemia.
Hepatic impairment: Thiazides should be used caution in patients With
impaired hepatic functionor progressive liver disease. as it may cause intra hepatic,
cholestasg, and since minor alterations of fluid and electrolyte balance may
precipitate hepatic coma.
Losazide is entraindicated for patients with severeheptic Impairment.
)ther: In patints receiving thiazides, hypersensitivity rections may occur with or
vithout a hisory of allergy or bronchial asthma. Exaerbation or activation of
ystemic lupu erythematosus has been reported with th use of thiazides.
Interaction with other medicinal products:
Losartan:
Rlfampicin ard fluconazole have been reported to reduce evels of active metabolite.
Phe clinical ccnsequences of these interactions have not ben evaluated.
ks with othe drugs that block angiotensin Il or its eficts, concomitant use of
potassium-spring diuretics (e.g. spirondactone, triarnterae, amiloride), potassium
supplements, Dr salt substitutes containing potassium lay lead to increases in
erum potassurn. Co-medication is not advisable.
ks with othel medicines which affect the excretion Of odium, lithium excretion
reduced. Therefore, serum lithium -levels should)e monitored carefully if
ithium salts ae to beco-administered with angiotensin Ireceptor antagonists.
Mhen angiotesin Il antagonists ace admimstered sirnultneously with NSAlDs (i.e.
elective CO)-2 inhibitors, acetylsalicylic at anti-flammatory doses) and
Ion-selective NSAIDs, attenuation of the antihypert€sive effect may occur.
Concomitant se of angiotensin Il antagonists or diureticand NSAlDs may lead to
in increased risk of worsening of renal function, including possible acute renal
failure, and an •increase in serum potassiurn, especia)y' in patients with poor
pre-existing renal function. The combination should be äministered with caution,
in I'le elderly Patients should be adequately hdrated and consideration
should be givn to monitoring renal functionafter initiatio of concomitant therapy,
Ind periodicäy thereafter.
In some patints with compromised renal function wh are being treated with
Ion-steroidal anti-inflammatory drugs, including sective cyclooxygenase-2
nhibitors, theco-administration of angiotensin Il receptr antagonists may result
n a further deterioration of renal function. These effécts re usually reversible.
)ther substartes inducing hypotension like tricycltc antiepressants, antipsychot-
cs, baclofene, arnifostlne: Concomitant use with thesedrugs that lower blood
pressure, as rain or side-effect, may increase the risk of ypotension.
Hydrochlorothiazide:
Mhen given concurrently. the following drugs may interat with thiazide diuretics:
Ucohol, bariiturates, narcotics or antidepressants: Ftentjauon of orthostatic
iypotension nay occur.
Antidiabetic Irugs (oral agents and insulin): The treatrent with a thiazide may
influence the glucose tolerance. Dosage adjustment of theantidiabetjc drug may be
required. Meiormin should be used v,'ith caution becase of the risk of lactic
acidosis Indued by possible functional renal failure linkd to hydrochlorothiazide.
Other antihyprrensive drugs: Additive effect.
Cholestyramie and colestipol resins: Absorptiom C hydrochlokothiazide is
impaired In he presence of anionic exchange resins Single doses of either
:holestyrarnire or colestjpol resins bind the hydroch10)thiazide and reduce its
ibsorption frcrn the gastrointestinal tract by up to 85 anc43 %, respectively.
Corticosteroid ACTH: Intensified electrolyte depletion, partularly hypokalaemia.
Pressor amines (e.g. adrenaline): Possible decreased reponse to pressor amines
jut not sufficent to preclude their use.
Skeletal musde relaxants, nondepolarizing (e.g. tubocunrine): Possible increased
esponsivenes to the muscle relaxant.
Lithium: Diurtlc agents reduce the renal clearance of litiurn and add a high risk
lithium toxcity; concomitant use is not recommended
Vledicinal prducts used in the treatment of gout (e.g. prbenecid, sulfinpyrazone,
Illopurinol): Dosage adjustment of uricosuriC Ined:inal products may be
Necessary sire hydrochlorothiazide may raise the leel of serum uric acid.
increase -in dosage of probenecid or sultinpyrazcne may be necessary.
Co-administration of a thiazide may increase the inclénce of hypersensitivity
reactions to alopurinol,
Anticholinerge agents (eg, atropine,' biperiden): Increae of the bioavailability to
hiazide-type diuretics- by decreasing gastrointestina motility and stomach
'mptyng race
Cytotoxic agets (e.g. cyclophosphamide, may reduce the
renal excretiQ1 Of cytotoxic medicinal products and potetiate their myelosuppres-
Sive, effects.
Salicylates: jn case of high dosages of Saiicylates, iydrochlorothiazide may
X'hance the bXic effect Of the salicylates on the central ervous system.
Wethyldopa: There have been isolated reports of haerolytic anaemia occurring
vith concomiant use of hydrochlorothiazide and methvtopa.
Ciclosporin: concomitant treatment with ciclospolln ray increase the risk of
hyperuricaema and gout-type complications.
Digitalis glyosides: Thiazide-induced hypokalaemta ohypornagnesaemia may
favour the onet or digitalis-induced cardiacarrhythrnias
Wedicinal -P•oducts affected by serum potassiurn disturbances: Periodic
nonitoring ci serum potassium and ECG-is recomrneded when Losazide is
administered Mith medicinal products affected by serur potassium disturbances
e.g. digitalis Jlycosides and antiarrhythmics) and Vith ie following torsades de
pointes (venncular medicinal pducts (including some
Not used in pregnancy, as it may cause injury and even death to the developing fetus.
Composition:
Losazide 50/12.5 mg F.C. Tablets:
Each F.C. tablet contains:
Losartan potassium
Hydrochlorothiazide .
Losazide 100/25 mg F.C. Tablets:
Each F.C. tablet contains:
Losartan potassium .
Hydrochlorothiazide .
50 mg
12.5 mg
100 mg
25 mg
Excipients: Microcrystalline cellulose, pregela nized starch, magnesium stearate,
sodium starch glycolate, hydroxypropyl cellulose, colloidal silicon dioxide.
Therapeutic Indications:
Treatment of essential hypertension in patients whose blood pressure is not
adequately controlled on losartan or hydrochlorothiazide monotherapy.
Posology and method of administration:
Losazide may be administered with other antihypertensive agents.
Losazide tablets should be swallowed with a glass of water.
Losazide may be administered with or without food.
Hypertension: Losazide tablets are not for use as initial therapy, but in patients
whose blood pressure is not adequately controlled by losartan potassium or
hydrochlorothiazide alone.
Dose titration with the individual components (losartan and hydrochlorothiazide) is
recommended.
When clinically appropriate, direct change from monotherapy to the fixed
combination may be considered in patients whose blood pressure is not
adequately controlled.
The usual maintenance dose is one tablet of Losazide 50 mg/ 12.5 mg (losartan
50 mg/HCTZ 12.5 mg) once daily. For patients who do not respond adequately to
Losazide 50 mg/ 12.5 mg, the dosage may be increased to one tablet of Losazide
100 mg/ 25 mg (losartan 100 mg/HCTZ 25 mg) once daily. The maximum dose is
one tablet of Losazide 100 mg/25 mg once daily. In general, the antihypertensive;
effect is attained within three to four weeks after initiation of therapy.
Use in patients with renal impairment and haemodialysis patients: No initial
dosage adjustment is necessary in patients With moderate renal impairment (i.e.
creatinine clearance 30 - 50 ml/min). Losazide tablets must not be used in
patients with severe renal impairment (i.e. creatinine clearance 30mI/min).
L.osazide tablets are not recommended for haemodialysis patients,
Use in patients with intravascular volume depletion: Volume and/or sodium
depletion should be corrected prior to administration of Losazide tablets.
Use in patients With hepatic impairment: Losazide is contraindicated in patients
with severe hepatic impairment.
Use in the elderly: Dosage adjustment is not usually necessary for the elderly.
Use in children and adolescents («18 years): There is no experience in children
and adolescents. Therefore, Losazide tablets should not be administered to
children and adolescents,
Contraindications:
-Hypersensitivity to losartan, sulphonamide-d lived substances (such as
- hydrochlorothiazide) 01 to any of the excipients.
- Therapy resistant hypokalaemia or hypercalcaemia.
- Severe hepatic impairment; chölestasis and biiiary obstructive disorders.
- Refractory hyponatraemia.
- Symptomatic hyperuricaemia/gout.
- Second and third trimester of pregnancy
- Lactation.
- Severe renal impairment (i.e. creatinine clearance 30 ml/min).
- Anuria,
The concomitant use of Losazide With altsklren-containing products
contraindicated in patients with diabetes mellitus or renal impairment (CFR
60ml/mn/1.73m2).
Special warnings and precautions for use:
Losartan:
is
Dual blockade of the renin-angiotensin-aldosterone system (RAAS): There •IS.
evidence that the concomitant use of ACE-inhibitors, angiotensin Il receptor
blockers or aliskiren increases the nsk of hypotension, hyperkalaemia and
decreased renal function (including acute renal failure)z Dual blockade of RA.AS

antiarrhythmics), hypokalaemia being a predisposing factor to torsades de pointes 

(ventricular tachycardia): 

- Class la antiarrythmics (e.g. quinidine, hydroquinidine, disopyramide). 

- Class Ill antiarrythmics (e.g. amoodarone, sotalol, dofetilide. ibutilide), 

Some antipsychotics (e.g. thioridazine, chlorpromazine. levomepromazine, 

trifluoperazine. cyamernazme, sulpiride, sultopride, amisuipride; tiapnde, 

pimozide, haloperidol, droperidol). 

Others (e.g. bepridil, cisapride, diphemanil, erythromycin IV, lofantrin, 

mizolastin, pentamidine, terfenadine, vincamine IV). 

Calcium salts: Thiazide diuretics may increase serum calcium levéls due to 

decreased excretion. If calcium supplements must be prescribed, serum calcium 

levels should be monitored and calcium dosage should be adjusted accordingly. 

Laboratory Test Interactions: Because of their effects on calcium metabolism, 

thiazides may interfere With tests for parathyroid function. 

Carbamazepine: Risk of symptomatic hyponatraemia. Clinical and biological 

monitoring are required. 

Iodine Contrast Media: In case of diuretic-induced dehydration, there. is an 

increased risk of acute renal failure, especially with high doses Of the iodine product. 

Patients should be rehvdrated before the administration. 

Amphotericin B (parenteral), corticosteroids, ACTH or stimulant laxatives or 

glycyrrhizin (found in liquorice'.• Hydrochlorothiazide may intensify electrolyte 

imbalance. particularly hypokalaemia. 

Pregnancy and Lactation: 

Pregnancy: Angiotensin Il Receptor antagonists (AllRA.s) should not be initiated, 

during pregnancy. Unless conunued AllRA therapy is considered essential, 

patients planning pregnancy should be changed to alternative anti-hypertensive 

treatments which have an established safety profile for use in pregnancy. When 

pregnancy is diagnosed, treatment with AllRAs should be stopped immediately, 

and, if appropriate, alternative therapy should be started. 

Hydrochlorothiazide may reduce both plasma volume and uteloplacental blood 

flow. Thiandes pass the placental barrier and are found in cord blood They may 

cause fetal electrolyte disturbances and possibly other reactions that have been 

observed in adults. Cases of thrombocytopenia in neonates and fetal or neonatal 

jaundice were reported after treating the mothers with thiazides. 

Lactation: It is not known whether losartan is excreted in human milk. However, 

losartan is excreted in the milk of lactating rats. Thiazides pass into human milk 

and may inhibit lactation. Because of the potential for adverse effects on the 

nursing infant, Losazide is contraindicated durjng breast-feeding. 

Effects on ability to drive and to use machines: 

No studies on the effects on the ability to dnve and to use machines have been 

performed. However, when driving vehicles or operating machinery lit 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. 

Undesirable effects; 

The adverse events below arc classified where appropriate by system organ class 

and frequency according to the following convention: 

Very common: 2 1/ 10 

Common: 

1/100, 1/10 

Uncommon: 1/1,000, s 1/100 

Eye disorders: 

Uncommon: Blurred vision, burning/stinging in the eye, conjunctivitis, decrease 

visual acuity. 

Ear and labyrinth disorders: 

Uncommon: Vertigos tinnitus. 

Cardiac disorders: 

Uncommon: Hypotension, orthostatic hypotension, sternalgia, angina ,pectoris, 

grade Il-AV block, - cerebrovascular event, myocardial infarction, palpitation, 

arrhythmias (atrial fibrillations, sinus bradycardia, tachycardia, ventricular 

tachycardia. ventricular fibrillation). 

Vascular disorders: 

Uncommon: Vasculitis. 

Respiratory, thoracic and mediastinal disorders: 

Common: Cough, upper respiratory infection, nasal congestion, sinusitis, sinus 

disorder. 

Uncommon: Pharyngeal discomfort, pharynglus, laryngitis, dyspnoea, bronchitis,) 

epistaxis, rhinitis, respiratory congestion. 

Gastrointestinal disorders: 

Common: Abdominal pain, nausea, diarrhoea, dyspepsia. 

Uncommon: Constipation, dental pain, dry mouth, flatulence, gastritis, vomiting. 

Hepato-biliary disorders: 

Not known: Liver function abnormalities. 

Skin and subcutaneous tissue disorders: 

Uncommon: Alopecia. dermatitis, dry skin, erythema, flushing, photosensitivity, 

pruritus, rash, urticaria, sweating. 

Musculoskeletal and connective tissue disorders: 

Common: Muscle cramp, back pain, leg pain, mya!gia 

Uncommon: Arm pain, joint swelling, knee pain, musculoskeletal pain* shoulder 

pain, stiffness, arthralgia, arthritis, coxalgia, fibromyalgia, muscle weakness. 

Not Known: Rhabdomyolysis. 

Renal and urinary disorders: 

Uncommon: Nocturia, urinary frequency, urinary tract infection. 

Reproductive system and breast disorders: 

Uncommon: Decreased libido, impotence. 

General disorders and administration site conditions: 

Common: Asthenia, fatigue, chest pain, 

Uncommon: Facial oedema, fever. 

Investigations: 

Common: Hyperkalaemia, mild reduction of haematocrit and haemoglobin. 

Uncommon: Mild increase In urea and creatinine serum levels. 

Very rare: Increase jn hepatic enzymes and bilirubin. 

Hydrochlorothiazide: 

Blood and lymphatic system disorders: 

Uncommon: AgranulocytosiS, aplastic anaemia, haemoiytic anaemia, leukopenia, 

purpura, thrombocytopenia. 

Immune system disorders: 

Rare: Anaphylactic reaction. 

Metabolism and nutrition disorders: 

Uncommon: Anorexia, hyperglycaemia, 

hyponatraemia. 

Psychiatric disorders: 

Uncommon: Insomnia. 

Nervous system disorders: 

Common: Cephalalgia. 

Eye disorders: 

hyperuricaemia, 

hypokalaemia, 

Rare: 

Very rare: 

Not known: 

1/10,000, 1/1,000 

1/10,000 

(cannot be estimated from the available data) 

Uncommon: Transient blurred vision, xanthopsia. 

Vascular disorders: 

Uncommon: Necrotizing angiitiS (vasculitiS, cutaneous vasculitiS). 

Respiratory, thoracic and mediastinal disorders: 

Uncommon: Respiratory distress including pneumonitis and pulmonary oedema. 

Gastrointestinal disorders: 

Uncommon: Sialoadenitis, spasms, stomach irritation, naUsea, vomiting, diarrhoea, 

constipation. 

Hepato-biliary disorders: 

Uncommon: Icterus (intrahepatic cholestatjs)ü pancreatitiS. 

Skin and subcutaneous tissue disorders: 

Uncommon: Photosensitivity, u:ticarja, toxic epidermal necrolysis: 

Musculoskeletal and connective tissue disorders: 

Uncommon: Muscle cramps. 

Renal and urinary disorders: 

Uncommon: Glycosuria, interstitial nephritis, renal dysfunction, renal failure. 

General disorders and administration site conditions: 

Uncommon: Fever, dizziness. 

Overdose: 

No specific information is available on the treatment of overdosage with Losartan 

potassium and Hydrochlorothiazide. Treatment is symptomatic and supportive 

Therapy witn Losazide should be discontinued and the patient observed closely. 

Suggested measures include induction of emesis if ingestion is recent and 

There are further adverse reactions as follows: 

Hepato-biliary disorders: 

Rare: Hepatitis. 

Investigations: 

Rare Hyperkalaemia, elevation of ALT. 

Additional adveise events that have been seen with one of the individual 

components and may be potential adverse events with losartan potassium/ 

hydrochlorothiazide are the following: 

Losartan: 

Blood and lymphatic system disorders: 

Uncommon: Anaemia. Henoch-SchönIein purpura. ecchymosis, haemolysis. 

Immune system disorders: 

Rare: Anaphylactic reactions, angioedema. urticaria. 

Metabolism and nutrition disorders: 

Uncommon: Anorexia. gout. 

Psychiatric disorders: 

Common: Insomnia. 

Uncommon: Anxiety, anxiety disorder, panic disorder, contusion, depression, 

abnormal dreams, sleep disorder, somnolence, memory impairrnent. 

Nervous system disorders: 

Common: Headache. dizziness. 

Uncommon: Nervousness. paraesthesia, peripheral neuropathy, migraine, 

syncope.„ 

correction of dehydration, electrolyte imbalance, hepatic coma and hypotension 

by established procedures. 

Losartan: 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 (hypokalaemja, hypochloraemia, hyponatraemia) 

and dehydration resulting from excessive diuresis. If digitalis has also been 

administered, hypokalaemia may accentuate cardiac arrhythmias. 

The degree to which hydrochlorothiazide is removed by haemodialysis has not 

Pharmacological properties: 

Pharmacodynamic properties: 

Pharmacotherapeutic group: Combination containing an angiotensin 

Il-receptor (type AT Il-antagonist and a thiazide diuretic, Antihypertensive. 

Losartan—hydrochlorothiazide: 

The components of losartan potassium / hydrochlorothiazide have been shown to 

have an additive effect on blood-pressure reduction, reducing blood pressure to a 

greater degree than either component alone. This effect is thought to be a result of 

the complimentary actions of both components. Further, as a result of its diuretic 

effect, hydrochlorothiazide increases plasma renin activity, increases aldosterone 

secretion, decreases serum potassium, and increases the levels of angiotensin Il, 

Administration of losartan blocks all the physiologically relevant actions of 

angiotensin Il and through inhibition of aldosterone could tend to attenuate the 

potassium loss associated with the diuretié. 

Losartan has been shown to have a mild and transient uricosuric effect. Hydrochlo- 

rothiazide has been shown to cause modest increases in uric acid; the combination 

of losartan and hydrochlorothiazide tends to attenuate the diuretic-induced 

hyperuricaemia. 

The antihypertensive effect of losartan potassium/hydrochlorothiazide is 

sustained for a 24-hour period. 

Losartan /Hydrochlorothiazide is effective in reducing blood pressure in males 

and females, blacks and non-blacks and in younger (K65 years) and older P65 

years) patients and is effective in all degrees of hypertension. 

Losartan: Losartan is a synthetically produced oral angiotensin-ll receptor (type ATI) 

antagonist. Angiotensin Il, a potent vasoconstrictor, is the primary active hormone of 

the renin-angiotensin system and an important determinant of the pathophysiology of 

hypertension. Angjotensin Il binds to the ATI receptor found in many tissues (e.g. 

vascular smooth muscle, adrenal gland, kidneys, and the heart) and elicits several 

important biological actions, including vasoconstriction and the release of aldosterone. 

Angiotensin Il also stimulates smooth-muscle cell proliferation. 

Losartan selectively blocks the ATI receptor. In vitro and in vivo, losartan and its 

pharmacologically active carboxylic acid metabolite E-3174 block all physiologically 

relevant actions of angiotensin Il, regardless of the source or route of its synthesis. 

Losartan does not have an agonist effect nor does it block other hormone receptors 

or ion channels important in cardiovascular regulation. Furthermore, losartan does 

not inhibit ACE (kininase Il), the enzyme that degrades bradykinin. Consequently, 

there is thus no increase in bradykinin-mediated undesirable effects. 

During the administration of losartan, the removal of the angiotensin Il negative 

feedback on renin secretion leads to increased plasma-renin activity (PRA). Increase 

in the PRA leads to an increase in angiotensin Il in plasma. Despite these increases, 

the antihypertensive activity and suppression of the plasma aldosterone 

concentration are maintained, indicating effective angiotensin Il receptor blockade. 

After the discontinuation of losartan, the PRA and angiotensin Il values fell within 

three days to the baseline values. 

Both losartan and its prinicipal active metabolite have a far greater affinity for the 

ATI receptor than for the AT 2 receptor. The active metabolite is 10 to 40 times more 

active than losartan on a weight for weight basis. 

In nondiabetic hypertensive patients with proteinuria, the administration of 

losartan potassium significantly reduces proteinuria, fractional excretion of 

albumin and IgG. Losartan maintains glomerular filtration rate and reduces 

filtration fraction. Generally losartan causes a decrease in serum uric acid (usually 

co.4 mg/dL) which was persistent in chronic therapy 

Losartan has no effect on autonomic reflexes and no sustained Fffect on plasma 

norepinephrine. 

In patients with left ventricular failure, 25 mg and 50 mg doses of losartan produced 

positive haemodynamic and neurohormonal effects characterized by an increase in 

cardiac index and decreases in pulmonary capillary wedge pressure, systemic 

vascular resistance, mean systemic arterial pressure and heart rate and a reduction in 

circulating levels of aldosterone and norepinephrine, respectively. The occurrence of 

hypotension was dose-related in these heart failure patients. 

Losartan is equally effective in males and females, and in younger (below age of 65 

years) and older hypertensive patients. 

Hydrochlorothiazide: Hydrochlorothiazide is a thiazide diuretic. The mechanism 

of the antihypertensive effect of thiazide diuretics is not fully known. Thiazides 

affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing 

excretion of sodium and chloride in approximately equivalent amounts. 

The diuretic action of hydrochlorothiazide reduces plasma volume, increases 

plasma renin activity and increases aldosterone secretion, with consequent 

increases in urinary potassium and bicarbonate loss, and decreases in serum 

potassium. The renin-aldosterone link is mediated by angiotensin Il and therefore 

coadminjstration of an angiotensin Il receptor antagonist tends to reverse the 

potassium loss associated With thiazide diuretics, 

After oral use, diuresis begins Within 2 hours, peaks in about 4 hours ancblasts 

about 6 to 12 hours and the antihypertensive effect persists for up to 24 hours. 

Pharmacokinetic properties: 

Absorption: 

Losartan: Following oral administration, losartan is well absorbed and undergoes 

first-pass metabolism, forming an active carboxylic acid metabolite and other 

inactive metabolites. The systemic bioavailability of losartan is approximately 33%. 

Mean peak concentrations of losartan and its active metabolite are reached in 1 

hour and in 3-4 hours, respectively. There was no clinically significant effect on the 

plasma concentration profile of losartan when the drug was administered with a 

standardized meal. 

Distribution: 

Losartan: Both losartan and its active metabolite are 99% bound to plasma 

proteins, primarily albumin. The volume of distribution of losartan is 34 litres. 

Studies in rats indicate that losartan crosses the blood-brain barrier poorly, if at all. 

Hydrochlorothiazide: Hydrochlorothiazide crosses the placental but not the 

blood-brain barrier and is excreted in breast milk. 

Biotransformation: 

Losartan: About 14% of an intravenously or orally administered dose of losartan is 

converted to its active metabolite. Following oral and intravenous administration of 

14C-IabelIed losartan potassium, circulating plasma radioactivity primarily is 

attributed to losartan and its active metabolite. Minimal conversion of losartan to its 

active metabolite was seen in about one percent of individuals studied. 

In addition to the active metabolite, inactive metabolites are formed, including two 

major metabolites formed by hydroxylation of the butyl side chain and a minor 

metabolite, an N-2 tetrazole glucuronide. 

Elimination: 

Losartan: Plasma clearance of losartan and its active metabolite is about 600 

mL/min and 50 mL/min, respectively. Renal clearance of losartan and its active 

metabolite is about 74 mL/min and 26 mL/min, respectively. When losartan is 

administered orally, about 4% of the dose is excreted unchanged in the urine, and 

about 6% Of the dose is excreted in the urine as active metabolite. The pharmacoki- 

netics of losartan and its active metabolite are linear with oral losartan potassium 

doses up to 200 mg. 

Following oral administration, plasma concentrations of losartan and its active 

metabolite decline polyexponentially with a terminal half-life of about 2 hours and 

6-9 hours respectively. During once-daily dosing with 100 mg, neither losartan nor 

its active metabolite accumulates significantly in plasma. 

Both biliary and urinary excretion contribute to the elimination of losartan and its 

metabolites. Following an oral dose of 14C-Iabelled losartan in man, about 35% of 

radioactivity is recovered in the urine and 58% in the faeces. 

Hydrochlorothiazide: Hydrochlorothiazide is not metabolised but is eliminated 

rapidly by the kidneys. When plasma levels have been followed for at least 24 

hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours. 

At least 61 % of the oral dose is eliminated unchanged within 24 hours. 

Characteristics in Patients: 

Losartan-HydrochIorothiazide: The plasma concentrations of losartan and its 

active metabolite and the absorption of hydrochlorothiazide in elderly 

hypertensives are not significantly different from those in young hypertensives. 

Losartan: Following oral administration in patients with mild to moderate alcoholic 

Cirrhosis of the liver, plasma concentrations of losartan and its active metabolite were, 

respectively, 5-fold and 1.7-fold greater than those seen in young male volunteers, 

Neither losartan nor the active metabolite can be removed by haemodialysis. 

Storage: 

Store at a temperature not exceeding 30•C. Protect from light. 

Packaging: 

Losazide 50/12.5 mg F.C.Tablets: Carton Box containing 1 blister (AL/opaque 

PVC) of 10 F.C. Tablets and inner leaflet. 

Losazide 100/25 mg F.C.TabIets: Carton Box containing 1 blister (AL/opaque 

PVC) of 10 F.C. Tablets and inner leaflet. 

•FOR. 

Issue date: August 2015 PMS: Black C. 

16 X 35 CM 56g,'m2 IILOOO PAM 000 003 

EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE 

EGYPTIAN INT. PHARMACEUTICAL INDUSTRIES CO. 

10th OF RAMADAN CITY , INDUSTRIAL AREA Bl, P.o. BOX: 149 TENTH, EGYPT