| Company Name |
| CID |
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| Therapeutic Group |
| ACE INH COMB+A-HYP/DIURET |
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| Pharmaceutical form |
| Tablets |
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| Package |
| Carton box containing 10 tablets( one Al /transparent PVC strip) + inner leaflet. |
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| Indications |
"Lisinopril and hydrochlorothiazide is indicated for the treatment of hypertension. These fixed-dose combinations are not indicated for initial therapy.
In using lisinopril and hydrochlorothiazide, consideration should be given to the fact that an angiotensin converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen vascular disease, and that available data are insufficient to show that lisinopril does not have a similar risk.
In considering use of lisinopril and hydrochlorothiazide it should be noted that black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to non-blacks.
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| Warning & Precautions |
| "Warnings: Linopril-H is contraindicated during pregnancy as it may cause injury and death to the developing baby General Lisinopril Anaphylactoid and Possibly Related Reactions: Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including lisinopril and hydrochlorothiazide) may be subject to a variety of adverse reactions, some of them serious. Angioedema: Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported rarely in patients treated with angiotensin converting enzyme inhibitors, including lisinopril. This may occur at any time during treatment. In such cases lisinopril and hydrochlorothiazide should be promptly discontinued and appropriate therapy and monitoring should be provided until complete and sustained resolution of signs and symptoms has occurred. In instances where swelling has been confined to the face and lips the condition has generally resolved without treatment, although antihistamines have be useful in relieving symptoms. Angioedema associated with laryngeal edema may be fatal. Where there involvement of the tongue, glottis or Iarynx, likely to cause airway obstruction, subcutaneous epinephrine solution 1:1000 (0.3 mL to 0.5 mL) and/or measures necessary to ensure a patent airway, should be promptly provided. Patients with a history of angioedema unrelated to ACE inhibitor therapy may at increased risk of angioedema while receiving an ACE inhibitor . Anaphylactoid reactions during desensitization: Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge. Anaphylactoid reactions during membrane exposure: Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption. Hypotension and Related Effects: Excessive hypotension was rarely seen in uncomplicated hypertensive patients but is a possible consequence of lisinopril use in salt/volume-depleted persons, such as those treated vigorously with diuretics or patients on dialysis. Syncope has been reported in 0.8 percent of patients receiving lisinopril and hydrochlorothiazide. In patients with hypertension receiving lisinopril alone, the incidence of syncope was 0.1 percent. The overall incidence of syncope may be reduced by proper titration of the individual components In patients with severe congestive heart failure, with or without associated renal insufficiency, excessive hypotension has been observed and may be associated with oliguria and/or progressive azotemia, and rarely with acute renal failure and/or death. Because of the potential fall in blood pressure in these patients, therapy should be started under very close medical supervision. Such patients should be followed closely for the first two weeks of treatment and whenever the dose of lisinopril and/or diuretic is increased. Similar considerations apply to patients with ischemic heart or cerebrovascular disease in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident. If hypotension occurs, the patient should be placed in supine position and, if necessary, receive an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further doses which usually can be given without difficulty once the blood pressure has increased after volume expansion. Neutropenia/Agranulocytosis: Another angiotensin converting enzyme inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression, rarely in uncomplicated patients but more frequently in patients with renal impairment, especially if they also have a collagen vascular disease. Available data from clinical trials of lisinopril are insufficient to show that lisinopril does not cause agranulocytosis at similar rates. Marketing experience has revealed rare cases of neutropenia and bone marrow depression in which a causal relationship to lisinopril cannot be excluded. Periodic monitoring of white blood cell counts in patients with collagen vascular disease and renal disease should be considered. Hepatic Failure: Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis, and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up. Hydrochlorothiazide Thiazides should be used with caution in severe renal disease. In patients with renal disease, thiazides may precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal function.Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.Sensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma.The possibility of exacerbation or activation of systemic lupus erythematosus has been reported.Lithium generally should not be given with thiazides Precautions: General Lisinopril Aortic Stenosis/Hypertrophic Cardiomyopathy: As with all vasodilators, lisinopril should be given with caution to patients with obstruction in the outflow tract of the left ventricle. Impaired Renal Function: As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe congestive heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with angiotensin converting enzyme inhibitors, including lisinopril, may be associated with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death. In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine may occur. Experience with another angiotensin converting enzyme inhibitor suggests that these increases are usually reversible upon discontinuation of lisinopril and/or diuretic therapy. In such patients renal function should be monitored during the first few weeks of therapy. Some hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in blood urea and serum creatinine, usually minor and transient, especially when lisinopril has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction of lisinopril and/or discontinuation of the diuretic may be required. Evaluation of the hypertensive patient should always include assessment of renal function. Hyperkalemia: In clinical trials hyperkalemia (serum potassium greater than 5.7 mEq/L) occurred in approximately 1.4 percent of hypertensive patients treated with lisinopril plus hydrochlorothiazide. In most cases these were isolated values, which resolved despite continued therapy. Hyperkalemia was not a cause of discontinuation of therapy. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements and/or potassium-containing salt substitutes, which should be used cautiously if at all with lisinopril and hydrochlorothiazide. Cough: Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, always resolving after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough. Surgery/Anesthesia: In patients undergoing major surgery or during anesthesia with agents that produce hypotension, lisinopril may block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion. Hydrochlorothiazide: Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals. All patients receiving thiazide therapy should be observed for clinical signs of fluid or electrolyte imbalance: namely, hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral fluids. Warning signs or symptoms of fluid and electrolyte imbalance, irrespective of cause, include dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting. Hypokalemia may develop, especially with brisk dieresis, when severe cirrhosis is present, or after prolonged therapy. Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia may cause cardiac arrhythmia and may also sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability). Because lisinopril reduces the production of aldosterone, concomitant therapy with lisinopril attenuates the diuretic-induced potassium loss Although any chloride deficit is generally mild and usually does not require specific treatment, except under extraordinary circumstances (as in liver disease or renal disease), chloride replacement may be required in the treatment of metabolic alkalosis. Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction, rather than administration of salt except in rare instances when the hyponatremia is life-threatening. In actual salt depletion, appropriate replacement is the therapy of choice. Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy. In diabetic patients dosage adjustments of insulin or oral hypoglycemic agents may be required. Hyperglycemia may occur with thiazide diuretics. Thus latent diabetes mellitus may become manifest during thiazide therapy. The antihypertensive effects of the drug may be enhanced in the postsympathectomy patients. If progressive renal impairment becomes evident consider withholding or discontinuing diuretic therapy. Thiazides have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia. Thiazides may decrease urinary calcium excretion. Thiazides may cause intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. 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 maybe associated with thiazide diuretic therapy. PREGNANCY AND LACTATION: Use in pregnancy: Linopril –H is contraindicated in the second and third trimesters of pregnancy. The use of Linopril –H is not recommended during the first trimester of pregnancy, When pregnancy is detected, lisinopril should be discontinued as soon as possible. ACE inhibitors can cause foetal and neonatal morbidity and mortality when administered to pregnant women during the second and third trimesters, Use of ACE inhibitors during the period has been associated with foetal and neonatal injury including hypotension, renal failure, hyperkalaemia and/or skull hypoplasia in the new-born. Maternal oligohydramnios, presumably representing decreased foetal renal function, has occurred and may result in limb contractures, craniofacial deformations and hypoplastic lung development. These adverse effects to the embryo and foetus do not appear to have resulted from intra-uterine ACE inhibitor exposure limited to the first trimesler The routine use of diuretics in otherwise healthy pregnant women is not recommended and exposes mother and foetus to unnecessary hazard including foetal or neonatal jaundice, thrombocytopenia and possibly other adverse reactions which have occurred in the adult If lisinopril is used during the first trimester of pregnancy, the patient should be informed of the potential hazard to the foetus. Should exposure to Linopril –H have occurred during the second or third trimesters of pregnancy, serial ultrasound examinations should be performed to assess the intra-amniotic environment. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the foetus has sustained irreversible injury. Infants whose mothers may have taken lisinopril should be closely observed for hypotension, oliguria and hyperkalaemia. lisinopril, which crosses the placenta, has been removed from the neonatal circulation by peritoneal dialysis with some clinical benefit, and theoretically may be removed by exchange transfusion. There is no experience with the removal of hydrochlorothiazide, which also crosses the placenta, from the neonatal circulation. Lactation It is not known whether lisinopril is secreted in human milk; however, thiazides do appear in human milk, Because of the potential for serious reactions from hydrochlorothiazide in breast-led infants, a decision should be made whether to discontinue breast feeding or to discontinue Linopril –H, taking into account the importance of the drug to the mother. Effects on ability to drive and use machines When driving vehicles or operating machines it should be taken into account that dizziness or tiredness may occur |
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| Product Type |
| Human |
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| Dosage |
"Essential hypertension
The usual dosage is one tablet. administered once daily. As with all other medications taken once daily, Linopril- H should be taken at approximately the same time each day.
In general, if the desired therapeutic effect cannot be achieved in a period of 2 to 4 weeks at this dose level, the dose can be increased to two tablets administered once daily.
Dosage in renal Insufficiency:
Thiazides may not be appropriate diuretics for use in patients with renal impairment and are ineffective at creatinine clearance values of 30 ml/min or below (i.e. moderate or severe renal insufficiency).
Linopril- H is not to be used as initial therapy in any patient with renal insufficiency
In patients with creatinine clearance of >30 and <80 ml/min, Linopril- H may be used, but only after titration of the individual compenents.
The recommended initial dose of lisinopril. when used alone, in mild renal insufficiency , is 5 to l0 mg.
Prior diuretic therapy
Symptomatic hypotension may occur following the initial dose of Linopril- H ; this is more likely in patients who are volume and/or salt depleted as a result of prior diuretic therapy. The diuretic therapy should be discontinued for 2-3 days prior to initiation of therapy with
Linopril- H if this is not possible, treatment should be started with lisinopril alone, in a 5 mg dose. Pediatric use
Safety and effectiveness in children have not been established.
Use In the elderly:
In clinical studies the efficacy and tolerability of lisinopril and hydrochlorothiazide, administered concomitantly, were similar in both elderly and younger hypertensive patients.
lisinopril, within a daily dosage range of 20 to 80 mg, was equally effective in elderly (65 years or older) and non-elderly hypertensive patients. In elderly hypertensive patients, monotherapy with lisinopril was as effective m reducing diastolic blood pressure as monotherapy with either hydrochlorothiazide or atenolol. In clinical studies. age did not affect the tolerability of lisinopril.
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| Adverse Reactions |
"Lisinopril and hydrochlorothiazide has been evaluated for safety in 930 patients, including 100 patients treated for 50 weeks or more.
In clinical trials with lisinopril and hydrochlorothiazide no adverse experiences peculiar to this combination drug have been observed. Adverse experiences that have occurred have been limited to those that have been previously reported with lisinopril or hydrochlorothiazide.
The most frequent clinical adverse experiences in controlled trials (including open label extensions) with any combination of lisinopril and hydrochlorothiazide were: dizziness (7.5 percent), headache (5.2 percent), cough (3.9 percent), fatigue (3.7 percent) and
orthostatic effects (3.2 percent), all of which were more common than in placebo-treated patients.
Generally, adverse experiences were mild and transient in nature; but regarding angioedema and excessive hypotension or syncope. Discontinuation of therapy due to adverse effects was required in 4.4 percent of patients, principally because of dizziness, cough, fatigue and muscle cramps.
Adverse experiences occurring in greater than one percent of patients treated with lisinopril plus hydrochlorothiazide in controlled clinical trials are shown below.
Percent of Patients in Controlled Studies Linopril-Hydrochlorothiazide
(n=930) Placebo
Incidence (n=207)
(discontinuation) Incidence
Dizziness 7.5 (0.8) 1.9
Headache 5.2 (0.3) 1.9
Cough 3.9 (0.6) 1.0
Fatigue 3.7 (0.4) 1.0
Orthostatic Effects 3.2 (0.1) 1.0
Diarrhea 2.5 (0.2) 2.4
Nausea 2.2 (0.1) 2.4
Upper Respiratory Infection 2.2 (0.0) 0.0
Muscle Cramps 2.0 (0.4) 05
Asthenia 1.8 (0.2) 1.0
Paresthesia 1.5 (0.1) 0.0
Hypotension 1.4 (0.3) 0.5
Vomiting 1.4 (01) 0.5
Dyspepsia 1.3 (0.0) 0.0
Rash 1.2 (0.1) 0.5
Impotence 1.2 (0.3) 0.0
Clinical adverse experiences occurring in 0.3 to 1.0 percent of patients in controlled trials included:
Body as a Whole: Chest pain, abdominal pain, syncope, chest discomfort, fever, trauma, virus infection. Cardiovascular: Palpitation, orthostatic hypotension.
Digestive: Gastrointestinal cramps, dry mouth, constipation, heartburn. Musculoskeletal: Back pain, shoulder pain, knee pain, back strain, myalgia, foot pain.
Nervous/Psychiatric: Decreased libido, vertigo, depression, somnolence.
Respiratory: Common cold, nasal congestion, influenza, bronchitis, pharyngeal pain, dyspnea, pulmonary congestion, chronic sinusitis, allergic rhinitis, pharyngeal discomfort. Skin: Flushing, pruritus, skin inflammation; diaphoresis.
Special Senses: Blurred vision, tinnitus, otalgia.
Urogenital: Urinary tract infection.
Angioedema: Angioedema has been reported in patients receiving lisinopril and hydrochlorothiazide, with an incidence higher in black than in non-black patients. Angioedema associated with laryngeal edema may be fatal. If angioedema of the face; extremities, lips, tongue, glottis and/or larynx occurs, treatment with lisinopril and hydrochlorothiazide should be discontinued and appropriate therapy instituted immediately. In rare cases, intestinal angioedema has been reported with angiotension converting enzyme inhibitors including lisinopril.
Hypotension: In clinical trials, adverse effects relating to hypotension occurred as follows: hypotension (1.4), orthostatic hypotension (0.5), other orthostatic effects (3.2). In addition syncope occurred in 0.8 percent of patients.
Cough: See PRECAUTIONS, Cough.
Clinical Laboratory Test Findings
Serum Electrolytes: See PRECAUTIONS.
Creatinine, Blood Urea Nitrogen: Minor reversible increases in blood urea nitrogen and serum creatinine were observed in patients with essential hypertension treated with lisinopril and hydrochlorothiazide. More marked increases have also been reported and were more likely to occur in patients with renal artery stenosis.
Serum Uric Acid, Glucose, Magnesium, Cholesterol, Triglycerides and Calcium: See PRECAUTIONS.
Hemoglobin and Hematocrit: Small decreases in hemoglobin and hematocrit (mean decreases of approximately 0.5 g percent and 1.5 vol percent, respectively) occurred frequently in hypertensive patients treated with lisinopril and hydrochlorothiazide but were rarely of clinical importance unless another cause of anemia coexisted. In clinical trials, 0.4 percent of patients discontinued therapy due to anemia.
Liver Function Tests: Rarely, elevations of liver enzymes and/or serum bilirubin have occurred (Hepatic Failure).
Other adverse reactions that have been reported with the individual components are listed below:
Lisinopril – In clinical trials adverse reactions which occurred with lisinopril were also seen with lisinopril and hydrochloro-thiazide. In addition, and since lisinopril has been marketed, the following adverse reactions have been reported with lisinopril and should be considered potential adverse reactions for lisinopril and hydrochlorothiazide:
Body as a Whole: Anaphylactoid reactions (Anaphylactoid and Possibly Related Reactions), malaise, edema, facial edema, pain, pelvic pain, flank pain, chills; Cardiovascular: Cardiac arrest, myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high risk patients (Hypotension), pulmonary embolism and infarction, worsening of heart failure, arrhythmias (including tachycardia, ventricular tachycardia, atrial fibrillation, bradycardia, and premature ventricular contractions), angina pectoris, transient ischemic attacks, paroxysmal nocturnal dyspnea, decreased blood pressure, peripheral edema, vasculitis;
Digestive: Pancreatitis, hepatitis (hepatocellular or cholestatic jaundice) , gastritis, anorexia, flatulence, increased salivation;
Endocrine: Diabetes mellitus;
Hematologic: Rare cases of neutropenia, thrombocytopenia, and bone marrow depression have been reported. Hemolytic anemia has been reported; a causal relationship to lisinopril cannot be excluded;
Metabolic: gout, weight loss, dehydration, fluid overload, weight gain;
Musculoskeletal: Arthritis, arthralgia, neck pain, hip pain, joint pain, leg pain, arm pain, lumbago;
Nervous System/Psychiatric: Ataxia, memory impairment, tremor, insomnia, stroke, nervousness, confusion, peripheral neuropathy (e.g., paresthesia, dysesthesia), spasm, hypersomnia, irritability;
Respiratory: Malignant lung neoplasms, hemoptysis, pulmonary edema, pulmonary infiltrates, eosinophilic pneumonitis, bronchospasm, asthma, pleural effusion, pneumonia, wheezing, orthopnea, painful respiration, epistaxis, laryngitis, sinusitis, pharyngitis, rhinitis, rhinorrhea, chest sound abnormalities;
Skin: Urticaria, alopecia, herpes zoster, photosensitivity, skin lesions, skin infections, pemphigus, erythema. Other severe skin reactions (including toxic epidermal necrolysis and Stevens-Johnson syndrome) have been reported rarely; causal relationship has not been established;
Special Senses: Visual loss, diplopia, photophobia, taste disturbances; Urogenital: Acute renal failure, oliguria, anuria, uremia, progressive azotemia, renal dysfunction, pyelonephritis, dysuria, breast pain.
Miscellaneous: A symptom complex has, been reported which may include a positive ANA, an elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia, fever,
vasculitis, leukocytosis, eosinophilia, photosensitivity, rash, and other dermatological manifestations.
Fetal/Neonatal Morbidity and Mortality: Pregnancy, Lisinopril, Fetal/Neonatal Morbidity and Mortality.
Hydrochlorothiazide – Body as a Whole: Weakness;
Digestive: Anorexia, gastric irritation, cramping, jaundice (intrahepatic cholestatic jaundice), pancreatitis, sialadenitis, constipation;
Hematologic: Leukopenia, agranulocytosis, thrombocytopenia, aplastic anemia, hemolytic anemia;
Musculoskeletal: Muscle spasm; Nervous System/Psychiatric: Restlessness;
Renal: Renal failure, renal dysfunction, interstitial nephritis
Skin: Erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis, alopecia;
Special Senses: Xanthopsia; Hypersensitivity: Purpura, photosensitivity, urticaria, necrotizing angiitis (vasculitis and cutaneous vasculitis), respiratory distress including pneumonitis and pulmonary edema, anaphylactic reactions.
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| Contra Indications |
"Linopril- H is contraindicated in patients with anuria.
Linopril- H is contraindicated in patients who are hypersensitive to any component of this product, in patients with a history of angioedema relating to previous treatment with an angiotensin-converting enzyme inhibitor and in patients with hereditary or idiopathic angioedema
Linopril- H is contraindicated in patients who are hypersensitive to other sulphonamide-derived drugs.
Linopril-H is contraindicated during pregnancy as it may cause injury and death to the developing baby . |
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| Drug Interactions |
"Potassium supplements, potassium-sparing agents or potassium-containing salt substitutes
The potassium losing effect of thiazide diuretics is usually attenuated by the potassium conserving effect of lisinopril. The use of potassium supplements, potassium-sparing agents or potassium containing salt substitutes, particularly in patients with impaired renal function, may lead to a significant increase in serum potassium, If concomitant use of Lisinopril –H and any of these agents is deemed appropriate, they should be used with caution and with frequent monitoring of serum potassium..
Lithium
Lithium generally should not be given with diuretics or ACE inhibitors. Diuretic agents and ACE inhibitors reduce the renal clearance of lithium and add a high risk of lithium toxicity. Refer to the prescribing information for lithium preparations before use of such preparations
Antihypertensive agents:
When combined with other antihypertensive agents, additive falls in blood pressure may occur.
Other agents:
Indomethacin may diminish the antihypertensive efficacy of concomitantly administered hydrochlorothiazide and lisinopril. In some patients with compromised renal function who are being treated with non-steroidal anti-inflammatory drugs (NSAlDs), the co-administration of lisinopril may result in a further deterioration in renal function.
Thiazides may increase the responsiveness to tubocurarine. |
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