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Lisinopril hydrochlorothiazide tablets

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Indications: For the treatment of hypertension. This compound is not suitable for the initial treatment of hypertension. It is suitable for patients who cannot be satisfactorily controlled by lisinopril or hydrochlorothiazide alone. It is also suitable for alternative treatment after the combination of two monotherapy has achieved satisfactory results.

Approval date: March 03, 2008

Modified on May 15, 2008

Please read the instructions carefully and use under the guidance of a physician.

【Drug Name】

Common name: lisinopril hydrochlorothiazide tablets

English name: Lisinopril and Hydrochlorothiazide Tablets

Chinese Pinyin: Lainuopuli Qinglüsaiqin Pian

[Ingredients]

This product is a compound preparation, and its components are each tablet containing 10mg of lisinopril and 12.5mg of hydrochlorothiazide

[Character] This product is white or off-white tablet.

[Specifications] Each tablet contains 10mg of lisinopril and 12.5mg of hydrochlorothiazide.

【Dosage】

Depending on the condition or individual differences, this product should be taken under the guidance or supervision of a physician. The dosage must follow the principle of individualization and be adjusted according to the effect. The dosage adjustment generally needs to be performed after 2-3 weeks of use.

When patients with lisinopril or hydrochlorothiazide alone cannot obtain sufficient antihypertensive effect, oral lisinopril hydrochlorothiazide tablets 10mg / 12.5mg, one tablet at a time, once a day, the dosage adjustment according to the blood pressure during the medication It depends.

Taking 25mg of hydrochlorothiazide daily can control blood pressure well, but patients with significant potassium loss may choose lisinopril-hydrochlorothiazide 10-12.5 to reduce potassium loss while having similar or better efficacy.

【Adverse reactions】

Safety evaluation of this product was performed on 930 patients abroad, of which 100 patients took this product for more than 50 weeks.
The side effects of lisinopril hydrochlorothiazide tablets are limited to the scope of using lisinopril or hydrochlorothiazide alone. The most common side effects in controlled trials (including open trials) were: dizziness (7.5%), headache (5.2%), cough (3.9%), fatigue (3.7%), and orthostatic hypotension (3.2%). The rates were higher than in the placebo group. Generally, side effects are mild and transient. The incidence of discontinuation due to side effects was 4.4%, mainly due to dizziness, cough, fatigue, and muscle cramps.
The side effects of using lisinopril-hydrochlorothiazide in a controlled trial with an incidence of more than 1% are shown in the following table:

The side effects of clinical trials in controlled trials between 0.3% and 1.0% were: whole body: chest pain, abdominal pain, syncope, chest discomfort, fever; cardiovascular system: palpitations, orthostatic hypotension; digestive system: gastrointestinal cramps or burning Sensation, dry mouth, constipation; motor skeletal system: shoulder and back pain, knee pain, myalgia; nervous system: hyposexuality, dizziness, depression, lethargy; respiratory system: nasal congestion, sore throat, dyspnea, pulmonary congestion, pharynx Discomfort; skin: redness, itching, and sweating. Sensory system: blurred vision and tinnitus.

Angioedema: Angioedema has been reported in patients taking lisinopril-hydrochlorothiazide. Although very rare, angioedema accompanied by pharyngeal edema may be fatal; angiotensin aminotransferase inhibitors may appear in the intestinal blood vessels Sexual edema. In case of angioedema of the face, terminal nerves, lips, tongue, glottis and / or larynx, lisinopril-hydrochlorothiazide should be stopped immediately and treated appropriately.

Hypotension: The side effects associated with hypotension in clinical trials were hypotension (1.4%), orthostatic hypotension (0.5%), and other orthostatic effects (3.2%). The incidence of syncope was 0.8%.

Cough: Possibly due to the inhibitory effect on the degradation of endogenous bradykinin, all ACE inhibitors have been reported to cause persistent cough, which can be relieved by stopping treatment. Cough due to ACE inhibitors should be considered in the diagnosis of cough.

Clinical laboratory results:

Serum electrolytes: Serum electrolytes should be tested regularly. When patients experience severe vomiting or intravenous infusion, special attention should be paid to the detection of serum and urine electrolyte levels. All patients who reuse thiazines should observe clinical signs of fluid or electrolyte imbalance: that is, hyponatremia, hypochlorine alkalosis, hypokalemia. Symptoms of fluid or electrolyte imbalance include, for example, dry mouth, thirst, weakness, restlessness, epilepsy, muscle pain or cramps, muscle weakness, hypotension, oliguria, tachycardia, and gastrointestinal disorders such as nausea and vomiting.

Creatinine, blood urinary nitrogen: Patients with essential hypertension treated with lisinopril-hydrochlorothiazide found a slight recoverable increase in blood urinary nitrogen and creatinine. Hemoglobin and hematocrit: A slight decrease in hemoglobin and hematocrit (average reductions of approximately 0.5% and 1.5% vol%, respectively). In clinical trials, 0.4% of patients discontinued treatment due to anemia.

Liver function tests: Rare, elevated liver enzymes and / or serum bilirubin. ACE inhibitors are rare with cholestatic jaundice or hepatitis as the initial symptom, and thereafter develop fulminant liver necrosis and even death. Therefore, if patients taking ACE inhibitors develop jaundice or a significant increase in liver enzymes, they should be discontinued and followed up appropriately.

The single-component side reactions may occur in lisinopril hydrochlorothiazide. Therefore, the following side reactions of lisinopril and hydrochlorothiazide can be used as a reference. The side reactions of the single component are listed below:

Lisinopril: whole body: allergies, chills; cardiovascular system: cardiac arrest, myocardial infarction or stroke (possibly secondary and sudden drop in blood pressure in high-risk groups), pulmonary infarction, exacerbation of heart failure, arrhythmia (including cardiac arrhythmias Tachycardia, atrial fibrillation, bradycardia, ventricular premature beats), angina pectoris, decreased blood pressure, vasculitis; digestive system: pancreatitis, hepatitis or liver damage (rare fulminant hepatic necrosis), gastritis, and anorexia and epigastric discomfort; blood System: Rare neutropenia, thrombocytopenia, and bone marrow suppression. Motor system: joint and muscle pain; nervous system: ataxia, memory loss, tremor, insomnia, peripheral neuropathy, drowsiness, irritability; respiratory system: dry cough, hemoptysis, bronchospasm, pleural effusion, pneumonia; skin: Rubella, baldness, herpes, light sensitivity, pemphigus, erythema. Rarely reported other severe skin reactions (including toxic epidermal necrosis and slackness, and Sjoy syndrome) with unclear etiology; special sensations: vision loss, diplopia, photophobia, taste disorders; urinary system: impaired renal function, progressive Nitrosemia, occasional acute renal failure.

A combination of several of these symptoms has also been reported.

Hydrochlorothiazide: whole body: weakness and allergic reactions; digestive system: anorexia and epigastric discomfort, jaundice (intrahepatic bile jaundice), pancreatitis, salivary glanditis, constipation; hematopoietic system: blood cell reduction, thrombocytopenia, aplastic anemia, Hemolytic anemia; Motor system: skeletal muscle spasm; Nervous system: Irritability; Urinary system: Renal insufficiency, Interstitial nephritis; Skin: Polymorphic erythema (including Stewart syndrome), Exfoliative dermatitis (including toxicity Epidermal necrosis slackness, hair loss); special sensation: yellow vision; other: vasculitis, pulmonary edema, etc.

[Taboo]

Those who are allergic to any component of this product; those who have experienced angioedema after treatment with ACE inhibitors; those with genetic or congenital angioedema; those without anuria and those allergic to sulfa drugs; pregnant women; bilateral renal artery stenosis By.

【Precautions】

Linopril

Aortic stenosis / hypertrophic cardiomyopathy: Patients with left ventricular outflow tract obstruction should use lisinopril with all vasodilators.

Renal function impairment: Due to the inhibitory effect of the renin-angiotensin-aldosterone system, some individuals may experience changes in renal function. Patients with severe congestive heart failure whose renal function is dependent on renin-angiotensin-aldosterone system activity, use of angiotensin-converting enzyme inhibitors, including lisinopril, may be accompanied by oliguria and / Or progressive azotemia, rare acute renal failure and death.

Hypertensive patients with unilateral renal artery stenosis may have elevated blood urea nitrogen and serum creatinine with lisinopril. Experience with another angiotensin-converting enzyme inhibitor has shown that blood urea nitrogen and blood creatinine can return to normal after discontinuation. In such patients, renal function should be monitored during the first few weeks of treatment.

When lisinopril is used in combination with diuretics, patients with hypertension who have no previous history of renal vascular disease may experience elevated blood urea nitrogen and serum creatinine, which are usually mild and transient. Patients with previous kidney injury have a higher incidence. Reduce or discontinue if necessary. Therefore, patients with hypertension should evaluate renal function. Hyperkalemia: Approximately 1.4% of hypertensive patients treated with lisinopril and hydrochlorothiazide produce hyperkalemia (serum potassium greater than 5.7 mEq / L). In most cases it disappears as treatment continues. Risk factors for hyperkalemia include: renal insufficiency, diabetes, and concomitant medication (see Drug Interactions for details). Cough: It may be caused by inhibiting the degradation of endogenous bradykinin. All ACE inhibitors have reported persistent cough, which can be relieved by stopping the drug. Cough due to ACE inhibitors should be considered in the diagnosis of cough.

Surgery / anaesthesia: Hypotension may occur when undergoing major surgery or a combination of anaesthetics, and once it occurs, it can be corrected by supplemental body fluids.

Neutropenia / Granulocytosis: Captopril is another angiotensin-converting enzyme inhibitor that has caused granulocytopenia and myelosuppression, and patients with renal impairment (especially with collagen at the same time) Vascular disease) is more common than non-complex patients. From the current data of patients taking lisinopril, it is uncertain whether its onset is related to the treatment of lisinopril. Patients with kidney disease and collagenous vascular disease should regularly monitor the number of white blood cells.

Hydrochlorothiazide

All patients taking thiazines should observe clinical signs of body fluid or electrolyte disturbances and regularly monitor serum electrolytes.

Some patients receiving thiazide treatment may experience elevated blood uric acid or increased gout.

Diabetics may need insulin dose adjustments or oral hypoglycemic drugs. The thiazide diuretics may increase blood sugar, which can make latent diabetes appear.

In patients after sympathectomy, the antihypertensive effect of the drug may be enhanced.

If progressive kidney damage occurs, consideration should be given to discontinuing thiazide therapy.

Thiazines increase the elimination of magnesium in the urine and therefore may cause hypomagnesemia.

Thiazines may reduce the elimination of urinary calcium. In the absence of calcium metabolism disorders, thiazines can cause intermittent and slight increases in serum calcium. The significant increase in blood calcium may be a response to hyperparathyroidism, and thiazide drugs should be stopped before relevant tests are performed.

Treatment with thiazide diuretics may be accompanied by elevated cholesterol and triglyceride levels.

Use with caution by athletes.

[Medication for pregnant and lactating women]

This product will adversely affect the fetus of pregnant women, so pregnant women and women who are planning to become pregnant are prohibited.

This product may be excreted through breast milk, so lactating women should not use it, or weigh the advantages and disadvantages, and stop breastfeeding while taking this product.

[Child medication]

The test was not performed and there are no reliable references.

[Medicine for the elderly]

Elderly patients should be careful in dose selection. Due to the high incidence of liver, kidney, and heart failure in elderly patients, they may take other drugs at the same time, generally starting from the lowest dose. A comparative pharmacokinetic study showed that AUC of lisinopril increased by approximately 120% in elderly patients. Hydrochlorothiazide AUC increased by approximately 80%.

【medicine interactions】

Non-steroidal anti-inflammatory drugs: Patients with renal insufficiency treated with non-steroidal anti-inflammatory drugs while taking lisinopril may cause further damage to renal function, but are generally reversible. There are reports that NSAIDs may reduce the blood pressure-lowering effect of ACE inhibitors, and the combination with hydrochlorothiazide may also affect its blood pressure-lowering and diuretic effects. Therefore, the combination of NSAIDs should consider drug-drug interactions.

Drugs that increase blood potassium: lisinopril can reduce potassium loss caused by thiazide diuretics. A combination of lisinopril with a potassium-containing diuretic (eg, spironolactone, ipritone, amlodipine, or amlomipramine), a potassium supplement, or a potassium-containing salt may cause a significant increase in blood potassium. Therefore, when taking the above drugs at the same time, blood potassium should be tested regularly.

Lithium: Potassium has been reported in combination with drugs that reduce sodium, including ACE inhibitors. Disabling lithium and ACE inhibitors, lithium poisoning is generally reversible. If lisinopril is used in combination with lithium, it is recommended that the serum lithium concentration be checked frequently. Diuretics reduce the renal clearance of lithium and increase the incidence of nephrotoxicity. Therefore, this product should be avoided in combination with lithium agent.

Alcohol, barbiturates or sedatives: combined with thiazide may cause orthostatic hypotension.

Diabetic drugs (oral drugs and insulin): Combination with hydrochlorothiazide may require adjustments to the dose of antidiabetic drugs.

Other antihypertensive drugs: Synergistic effects with hydrochlorothiazide.

Cholestyramine and lipid-lowering resins: Anion exchange resins can affect hydrochlorothiazide absorption; taking a single dose of cholestimine and lipid-lowering resins can reduce gastrointestinal absorption by 85% and 43%, respectively.

Corticosteroids: ACTH-enhancing electrolyte loss, especially hypokalemia.

Hypertensive amines (eg, norepinephrine): may reduce the response to hypertensive amines, but do not need to be discontinued.

Skeletal muscle relaxants: Non-depolarizing relaxants (eg, sarcophylline): May enhance the muscle relaxant response.

Other drugs: There are no clinically significant side effects of lisinopril in combination with nitrates and / or digoxin. The combination of lisinopril with propranolol, digoxin, and hydrochlorothiazide has no clinically significant pharmacokinetic effect. Food does not affect the bioavailability of lisinopril.

[Drug overdose]

Symptomatic and supportive treatment. Stop lisinopril-hydrochlorothiazide and observe the patient. Suggested measures include vomiting and / or gastric lavage and taking appropriate measures to correct dehydration, electrolyte imbalances, and hypotension.

Linopril

A single dose of lisinopril 20 mg / kg was not fatal to rats, and 1 of 20 mice died. The most likely manifestation of drug overdose is hypotension, which is usually given by intravenous infusion of saline. Lisinopril can be cleared by hemodialysis.

Hydrochlorothiazide

Rats and mice did not die at a single oral dose of 10 mg / kg hydrochlorothiazide. The most common symptoms are caused by electrolyte deficiency (hypokalemia, hypochloremia, hyponatremia) and dehydration due to excessive diuretic effects. If digitalis is taken at the same time, hypokalemia may cause arrhythmia.

【Clinical Trials】

In clinical studies conducted abroad, the combined use of lisinopril and hydrochlorothiazide to reduce blood pressure is almost additive. The hypotensive effect of lisinopril hydrochlorothiazide can be maintained for 24 hours in most patients.

In a controlled clinical trial, lisinopril-hydrochlorothiazide 20-12.5 and lisinopril-hydrochlorothiazide 20-25 have similar hypotensive effects, suggesting that many use of lisinopril-hydrochlorothiazide 20-25 can effectively control blood pressure Patients, it may be possible to control the condition by applying 20-12.5 in the future.

When taking lisinopril and hydrochlorothiazide at the same time, the bioavailability changed only slightly or was not affected. Lisinopril hydrochlorothiazide tablets are bioequivalent when taken simultaneously with two drugs.

[Pharmacology and Toxicology]

1. Pharmacological effects:

As a diuretic, hydrochlorothiazide can increase plasma renin activity and aldosterone secretion, and lower blood pressure. Lisinopril reduces aldosterone secretion and lowers blood pressure by inhibiting angiotensin-converting enzyme (ACE). The combined use of lisinopril and hydrochlorothiazide can lower blood pressure more effectively and offset the blood potassium reduction effect of diuretics.

2. Carcinogenicity, mutagenicity and reproductive toxicity:

Lisinopril-hydrochlorothiazide: Completed experiments have shown that lisinopril-hydrochlorothiazide has no significant mutagenic effect. Existing data show that lisinopril has no obvious carcinogenicity and no significant side effects on fertility at higher than effective doses.

Hydrochlorothiazide: In two years of testing, no obvious carcinogenicity was found, and routine tests showed no significant mutagenicity and reproductive toxicity.

【Pharmacokinetics】

When taking lisinopril and hydrochlorothiazide at the same time, the bioavailability changed only slightly or was not affected. Lisinopril hydrochlorothiazide tablets are bioequivalent when taken simultaneously with two drugs.

Lisinopril pharmacokinetics

By taking lisinopril orally, the peak plasma concentration was reached in about 7 hours. Lisinopril is eliminated directly from the urine in the form of the original drug. According to the urine recovery rate, taking lisinopril dose of 5-80mg, the absorption degree is about 25%, but the individual difference is large (6% ~ 60%). Gastrointestinal foods do not affect lisinopril absorption.

With multiple doses of lisinopril, the effective accumulation half-life is 12 hours.

Since lisinopril is eliminated mainly through the kidney, renal function impairment will reduce the elimination of lisinopril, but it is of clinical importance only when the glomerular filtration rate is below 30 ml / min. When the glomerular filtration rate is higher than 30 ml / min, the elimination half-life is only slightly changed. However, patients with severe renal impairment will increase the peak and trough blood levels of lisinopril, prolong the time to reach the peak, and prolong the time to reach steady state. Generally, the plasma concentration and the area under the curve (AUC) of elderly patients are higher (about 2 times) than those of young patients. Lisinopril can be cleared by hemodialysis.

Studies in rats have shown that lisinopril is essentially unable to cross the blood-brain barrier. Rats taking multiple doses of lisinopril did not accumulate in any tissue. However, radioactively labeled 14C lisinopril was detected in the milk of lactating rats. After taking radiolabeled drugs, pregnant rats were subjected to systemic examination and autoradiography. Radioactivity was detected in the placenta, but not in the fetus.

Hydrochlorothiazide pharmacokinetics

Diuretic effect begins within 2 hours after oral administration. The peak of effect appears in about 4 hours, and the effect can be maintained for about 6-12 hours.

Hydrochlorothiazide is not metabolized but is rapidly eliminated by the kidneys. Plasma concentrations were monitored for more than 24 hours, and plasma half-life varied from 5.6 to 14.8 hours. At least 61% of the drug is eliminated in its original form within 24 hours of oral administration. Hydrochlorothiazide passes through the placenta but does not cross the blood-brain barrier.

[Storage] shading, sealed, and stored in a cool (not more than 20 ℃) dry place.

[Packaging] Aluminum plastic, 10 pieces / board, 1 plate / box or 2 plates / box.

[Validity] Tentatively 24 months

[Executive Standard] YBH01852008

[Approval number] National Medicine Standard H20080080

【manufacturer】