Hyzaar/Hyzaar Plus/Hyzaar Forte

Hyzaar/Hyzaar Plus/Hyzaar Forte

losartan + hydrochlorothiazide

Manufacturer:

Organon

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Losartan potassium, hydrochlorothiazide.
Description
Hyzaar: Each tablet contains losartan potassium 50 mg and hydrochlorothiazide 12.5 mg.
Hyzaar Plus: Each tablet contains losartan potassium 100 mg and hydrochlorothiazide 12.5 mg.
Hyzaar Forte: Each tablet contains losartan potassium 100 mg and hydrochlorothiazide 25 mg.
Action
Therapeutic Class: Hyzaar/Hyzaar Plus/Hyzaar Forte (losartan potassium and hydrochlorothiazide) is the first combination of an angiotensin II receptor (type AT1) antagonist and a diuretic. HYZAAR also provides a reduction in the risk of stroke in hypertensive patients with left ventricular hypertrophy.
Indications/Uses
Hypertension: HYZAAR/HYZAAR PLUS/HYZAAR FORTE is indicated for the treatment of hypertension for patients in whom combination therapy is appropriate.
Hypertensive Patients with Left Ventricular Hypertrophy: HYZAAR/HYZAAR PLUS/HYZAAR FORTE is a combination of losartan (COZAAR) and hydrochlorothiazide. In patients with hypertension and left ventricular hypertrophy, losartan, often in combination with hydrochlorothiazide, reduces the risk of stroke in hypertensive patients with left ventricular hypertrophy (see RACE under PRECAUTIONS).
Dosage/Direction for Use
HYZAAR may be administered with other antihypertensive agents.
HYZAAR may be administered with or without food.
Hypertension: The usual starting and maintenance dose is one tablet of HYZAAR (losartan potassium 50 mg/hydrochlorothiazide 12.5 mg) once daily. For patients who do not respond adequately to HYZAAR, the dosage may be increased to one tablet of HYZAAR FORTE (losartan potassium 100 mg/hydrochlorothiazide 25 mg) once daily or two tablets of HYZAAR once daily. The maximum dose is one tablet of HYZAAR FORTE or two tablets of HYZAAR once daily. In general, the antihypertensive effect is attained within three weeks after initiation of therapy. HYZAAR PLUS (losartan potassium 100 mg/hydrochlorothiazide 12.5 mg) is available for those patients titrated to 100 mg of COZAAR who require additional blood pressure control.
HYZAAR/HYZAAR PLUS/HYZAAR FORTE should not be initiated in patients who are intravascularly volume-depleted (e.g., those treated with high-dose diuretics).
HYZAAR/HYZAAR PLUS/HYZAAR FORTE is not recommended for patients with severe renal impairment (creatinine clearance ≤30 mL/min) or for patients with hepatic impairment.
No initial dosage adjustment for HYZAAR is necessary for elderly patients. HYZAAR FORTE/HYZAAR PLUS should not be used as the initial dose in elderly patients.
Reduction in the Risk of Stroke in Hypertensive Patients with Left Ventricular Hypertrophy: The usual starting dose is 50 mg of losartan once daily. If goal blood pressure is not reached with losartan 50 mg, therapy should be titrated using a combination of losartan and a low dose of hydrochlorothiazide (12.5 mg) and, if needed, the dose should then be increased to losartan 100 mg and hydrochlorothiazide 12.5 mg once daily. If necessary, the dose should be increased to losartan 100 mg and hydrochlorothiazide 25 mg once daily. HYZAAR, HYZAAR PLUS and HYZAAR FORTE are suitable alternative formulations in patients who would otherwise be treated concomitantly with losartan plus hydrochlorothiazide.
Overdosage
No specific information is available on the treatment of overdosage with HYZAAR/HYZAAR PLUS/HYZAAR FORTE. Treatment is symptomatic and supportive. Therapy with HYZAAR/HYZAAR PLUS/HYZAAR FORTE should be discontinued and the patient observed closely. Suggested measures include induction of emesis if ingestion is recent and 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 hemodialysis.
Hydrochlorothiazide: The most common signs and symptoms observed are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias.
The degree to which hydrochlorothiazide is removed by hemodialysis has not been established.
Contraindications
HYZAAR/HYZAAR PLUS/HYZAAR FORTE is contraindicated in: patients who are hypersensitive to any component of this product; patients with anuria; patients who are hypersensitive to other sulfonamide-derived drugs.
The concomitant use of HYZAAR PLUS/HYZAAR FORTE with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) (see INTERACTIONS).
Warnings
Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. When pregnancy is detected, discontinue HYZAAR/HYZAAR PLUS/HYZAAR FORTE as soon as possible.
When used in pregnancy during the 2nd and 3rd trimesters, drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus. When pregnancy is detected, Hyzaar/Hyzaar Plus/Hyzaar Forte should be discontinued as soon as possible.
Special Precautions
Losartan-Hydrochlorothiazide: Fetal Toxicity: Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure and death. When pregnancy is detected, discontinue HYZAAR as soon as possible. See PREGNANCY under Use in Pregnancy & Lactation.
Hypersensitivity: Angioedema. (See SIDE EFFECTS.)
Hepatic and Renal Impairment: HYZAAR/HYZAAR PLUS/HYZAAR FORTE is not recommended for patients with hepatic impairment or severe renal impairment (creatinine clearance ≤30 mL/min) (see DOSAGE & ADMINISTRATION).
Losartan: Renal Function Impairment: As a consequence of inhibiting the renin-angiotensin system, changes in renal function including renal failure have been reported in susceptible individuals; these changes in renal function may be reversible upon discontinuation of therapy.
Other drugs that affect the renin-angiotensin system may increase blood urea and serum creatinine in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney. Similar effects have been reported with losartan; these changes in renal function may be reversible upon discontinuation of therapy.
Increases in Serum Potassium: Concomitant use of other drugs that may increase serum potassium may lead to hyperkalemia (see INTERACTIONS).
Dual blockade of the renin-angiotensin-aldosterone system (RAAS): There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see INTERACTIONS).
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 II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.
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, hyponatremia, hypochloremic alkalosis, hypomagnesemia or hypokalemia which may occur during intercurrent diarrhea or vomiting. Periodic determination of serum electrolytes should be performed at appropriate intervals in such patients.
Metabolic and endocrine effects: Thiazide therapy may impair glucose tolerance. Dosage adjustment of antidiabetic agents, including insulin, may be required (see INTERACTIONS).
Thiazides may decrease urinary calcium excretion and may cause intermittent and slight elevation of serum calcium. Marked hypercalcemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.
Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.
Thiazide therapy may precipitate hyperuricemia and/or gout in certain patients. Because losartan decreases uric acid, losartan in combination with hydrochlorothiazide attenuates the diuretic-induced hyperuricemia.
Non-melanoma skin cancer: An increased risk of non-melanoma skin cancer (basal cell carcinoma [BCC] and squamous cell carcinoma [SCC]) with increasing cumulative dose of hydrochlorothiazide has been observed in epidemiological studies. Photosensitizing actions of hydrochlorothiazide could act as a possible mechanism for non-melanoma skin cancer.
Patients taking hydrochlorothiazide should be informed of the risk of non-melanoma skin cancer and advised to take preventive measures to reduce sun and artificial UVA exposure. Patients should regularly check their skin for new lesions and promptly report suspicious skin lesions to their physicians for evaluation. The use of hydrochlorothiazide may also need to be reconsidered in patients who have experienced previous non-melanoma skin cancer. (See also SIDE EFFECTS.)
Other: In patients receiving thiazides, 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.
RACE: Based on the LIFE (Losartan Intervention For Endpoint reduction in hypertension) study, the benefits of losartan on cardiovascular morbidity and mortality compared to atenolol do not apply to Black patients with hypertension and left ventricular hypertrophy although both treatment regimens effectively lowered blood pressure in Black patients. In the overall LIFE study population (n=9193), treatment with losartan resulted in a 13.0% risk reduction (p=0.021) as compared to atenolol for patients reaching the primary composite endpoint of the combined incidence of cardiovascular death, stroke and myocardial infarction. In this study, losartan decreased the risk of cardiovascular morbidity and mortality compared to atenolol in non-Black, hypertensive patients with left ventricular hypertrophy (n=8660) as measured by the primary endpoint of the combined incidence of cardiovascular death, stroke and myocardial infarction (p=0.003). In this study, however, Black patients treated with atenolol were at lower risk of experiencing the primary composite endpoint compared with Black patients treated with losartan (p=0.03). In the subgroup of Black patients (n=533, 6% of the LIFE study patients), there were 29 primary endpoints among 263 patients on atenolol (11%, 25.9/1000 patient-years) and 46 primary endpoints among 270 patients (17%, 41.8/1000 patient-years) on losartan.
Use in Children: Safety and effectiveness in children have not been established.
Neonates with a history of in utero exposure to HYZAAR: If oliguria or hypotension occur, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.
Use in the Elderly: In clinical studies, there were no clinically significant differences in the efficacy and safety profiles of losartan-hydrochlorothiazide in older (≥65 years) and younger patients (<65 years).
Use In Pregnancy & Lactation
PREGNANCY: Although there is no experience with the use of HYZAAR/HYZAAR PLUS/HYZAAR FORTE in pregnant women, animal studies with losartan potassium have demonstrated fetal and neonatal injury and death, the mechanism of which is believed to be pharmacologically mediated through effects on the renin-angiotensin system. In humans, fetal renal perfusion, which is dependent upon the development of the renin-angiotensin system, begins in the second trimester; thus, risk to the fetus increases if HYZAAR/HYZAAR PLUS/HYZAAR FORTE is administered during the second or third trimesters of pregnancy.
Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure and death. When pregnancy is detected, discontinue HYZAAR as soon as possible.
These adverse outcomes are usually associated with the use of these drugs in the second and third trimesters of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.
In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue HYZAAR, unless it is considered life-saving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to HYZAAR for hypotension, oliguria and hyperkalemia.
Thiazides cross the placental barrier and appear in cord blood. The routine use of diuretics in otherwise healthy pregnant women is not recommended and exposes mother and fetus to unnecessary hazard including fetal or neonatal jaundice, thrombocytopenia and possibly other adverse reactions which have occurred in the adult. Diuretics do not prevent development of toxemia of pregnancy and there is no satisfactory evidence that they are useful in the treatment of toxemia.
NURSING MOTHERS: It is not known whether losartan is excreted in human milk. Thiazides appear in human milk. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Side Effects
In clinical trials with losartan potassium-hydrochlorothiazide, no adverse experiences peculiar to this combination drug have been observed. Adverse experiences have been limited to those that were reported previously with losartan potassium and/or hydrochlorothiazide. The overall incidence of adverse experiences reported with the combination was comparable to placebo. The percentage of discontinuations of therapy was also comparable to placebo.
In general, treatment with losartan potassium-hydrochlorothiazide was well tolerated. For the most part, adverse experiences have been mild and transient in nature and have not required discontinuation of therapy.
In controlled clinical trials for essential hypertension, dizziness was the only adverse experience reported as drug-related that occurred with an incidence greater than placebo in one percent or more of patients treated with losartan potassium-hydrochlorothiazide.
In a controlled clinical trial in hypertensive patients with left ventricular hypertrophy, losartan, often in combination with hydrochlorothiazide, was generally well tolerated. The most common drug-related side effects were dizziness, asthenia/fatigue and vertigo.
The following additional adverse reactions have been reported in post-marketing experience with HYZAAR and/or in clinical trials or post-marketing use with the individual components: Neoplasms Benign, malignant and unspecified (incl cysts and polyps): Non-melanoma skin cancer (basal cell carcinoma, squamous cell carcinoma).
Blood and lymphatic system disorders: Thrombocytopenia, anemia, aplastic and hemolytic anemia, leukopenia, agranulocytosis.
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 drugs including ACE inhibitors.
Metabolism and nutrition disorders: Anorexia, hyperglycemia, hyperuricemia, electrolyte imbalance including hyponatremia and hypokalemia.
Psychiatric disorders: Insomnia, restlessness.
Nervous system disorders: Dysgeusia, headache, migraine, paraesthesias.
Eye disorders: Xanthopsia, transient blurred vision.
Cardiac disorders: Palpitation, tachycardia.
Vascular disorders: Dose-related orthostatic effects, necrotizing angiitis (vasculitis) (cutaneous vasculitis).
Respiratory, thoracic and mediastinal disorders: Cough, nasal congestion, pharyngitis, sinus disorder, upper respiratory infection, respiratory distress (including pneumonitis and pulmonary edema).
Gastrointestinal disorders: Dyspepsia, abdominal pain, gastric irritation, cramping, diarrhea, constipation, nausea, vomiting, pancreatitis, sialoadenitis.
Hepato-biliary disorders: Hepatitis, jaundice (intrahepatic cholestatic jaundice).
Skin and subcutaneous tissue disorders: Rash, pruritus, purpura (including Henoch-Schoenlein purpura), toxic epidermal necrolysis, urticaria, erythroderma, photosensitivity, cutaneous lupus erythematosus.
Musculoskeletal and connective tissue disorders: Back pain, muscle cramps, muscle spasm, myalgia, arthralgia.
Renal and urinary disorders: Glycosuria, renal dysfunction, interstitial nephritis, renal failure.
Reproductive system and breast disorders: Erectile dysfunction/impotence.
General Disorders and administration site conditions: Chest pain, edema/swelling, malaise, fever, weakness.
Investigations: Liver function abnormalities.
Description of Selected Side Effects: Non-melanoma skin cancer (basal cell carcinoma, squamous cell carcinoma): Based on available data from epidemiological studies, a cumulative dose-dependent association between hydrochlorothiazide and non-melanoma skin cancer (BCC and SCC) has been observed.
The largest study included a population comprised of 71,533 cases of BCC and 8,629 cases of SCC matched to 1,430,833 and 172,462 population controls, respectively. High cumulative hydrochlorothiazide use (≥ 50,000 mg) was associated with an adjusted odds ratio (OR) of 1.29 (95% CI: 1.23-1.35) for BCC and 3.98 (95% CI: 3.68-4.31) for SCC. A cumulative dose-response relationship was observed for both BCC and SCC. Another study evaluated the association between lip cancer (SCC) and exposure to hydrochlorothiazide: 633 cases of lip cancer were matched with 63,067 population controls. A cumulative dose-response relationship was demonstrated with an adjusted OR of 2.1 (95% CI: 1.7-2.6) for ever-use, increasing to an OR of 3.9 (95% CI: 3.0-4.9) for high use (≥ 25,000 mg) and an OR of 7.7 (95% CI: 5.7-10.5) for the highest cumulative dose (≥ 100,000 mg).
Laboratory Test Findings: In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with administration of losartan-hydrochlorothiazide. Hyperkalemia (serum potassium >5.5 mEq/L) occurred in 0.7% of patients, but in these trials, discontinuation of losartan-hydrochlorothiazide due to hyperkalemia was not necessary. Elevations of alanine aminotransferase (ALT) occurred rarely and usually resolved upon discontinuation of therapy.
Drug Interactions
Losartan: In clinical pharmacokinetic trials, no drug interactions of clinical significance have been identified with hydrochlorothiazide, digoxin, warfarin, cimetidine, phenobarbital (see Alcohol, Barbiturates or Narcotics under Hydrochlorothiazide as follows), ketoconazole and erythromycin. Rifampin and fluconazole have been reported to reduce levels of active metabolite. The clinical consequences of these interactions have not been evaluated.
As with other drugs that block angiotensin II or its effects, concomitant use of potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements or salt substitutes containing potassium, or other drugs that may increase serum potassium (e.g., trimethoprim-containing products) may lead to increases in serum potassium.
As with other drugs which affect the excretion of sodium, lithium excretion may be reduced. Therefore, serum lithium levels should be monitored carefully if lithium salts are to be co-administered with angiotensin II receptor antagonists.
Non-steroidal anti-inflammatory drugs (NSAIDs) including selective cyclooxygenase-2 (COX-2) inhibitors may reduce the effect of diuretics and other antihypertensive drugs. Therefore, the antihypertensive effect of angiotensin II receptor antagonists or ACE inhibitors may be attenuated by NSAIDs including selective COX-2 inhibitors.
In some patients with compromised renal function (e.g., elderly patients or patients who are volume-depleted, including those on diuretic therapy) who are being treated with non-steroidal anti-inflammatory drugs, including selective cyclooxygenase-2 inhibitors, the co-administration of angiotensin II receptor antagonists or ACE inhibitors may result in a further deterioration of renal function including possible acute renal failure. These effects are usually reversible. Therefore, the combination should be administered with caution in patients with compromised renal function.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS) with angiotensin receptor blockers, ACE inhibitors or aliskiren is associated with increased risks of hypotension, syncope, hyperkalemia and changes in renal function (including acute renal failure) as compared to monotherapy. Closely monitor blood pressure, renal function and electrolytes in patients on HYZAAR/HYZAAR PLUS/HYZAAR FORTE and other agents that affect the RAAS (see CONTRAINDICATIONS and PRECAUTIONS).
Hydrochlorothiazide: When given concurrently, the following drugs may interact with thiazide diuretics: Alcohol, barbiturates or narcotics: Potentiation of orthostatic hypotension may occur.
Antidiabetic drugs (oral agents and insulin): Dosage adjustment of the antidiabetic drug may be required.
Other antihypertensive drugs: Additive effect.
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 percent, respectively.
Corticosteroids, ACTH or glycyrrhizin (found in liquorice): Intensified electrolyte depletion, particularly hypokalemia.
Pressor amines (e.g., adrenaline): Possible decreased response to pressor amines but not sufficient to preclude their use.
Skeletal muscle relaxants, nondepolarizing (e.g., tubocurarine): Possible increased responsiveness to the muscle relaxant.
Lithium: Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity; concomitant use is not recommended. Refer to the package inserts for lithium preparations before use of such preparations.
Non-Steroidal Anti-inflammatory Drugs Including Cyclooxygenase-2 Inhibitors: The administration of a non-steroidal anti-inflammatory agent including a selective cyclooxygenase-2 inhibitor can reduce the diuretic, natriuretic and antihypertensive effects of diuretics (see Losartan as mentioned previously).
Drug/Laboratory Test Interactions: Because of their effects on calcium metabolism, thiazides may interfere with tests for parathyroid function (see PRECAUTIONS).
Storage
Store below 30°C.
ATC Classification
C09DA01 - losartan and diuretics ; Belongs to the class of angiotensin II receptor blockers (ARBs) in combination with diuretics. Used in the treatment of cardiovascular disease.
Presentation/Packing
Hyzaar: Tab 30's. Hyzaar Plus: Tab 30's. Hyzaar Forte: Tab 30's.
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