Quadropril^® (Tablets) Instructions for Use

Marketing Authorization Holder

Teva Pharmaceutical Industries, Ltd. (Israel)

Manufactured By

Merckle, GmbH (Germany)

ATC Code

C09AA11 (Spirapril)

Active Substance

Spirapril (Rec.INN registered by WHO)

Dosage Form

Quadropril®

Tablets 6 mg: 30 pcs.

Dosage Form, Packaging, and Composition

Tablets from light pink with marbling to pink with an orange tint with marbling, round, with beveled edges, with a smooth surface and a score on one side; on the side with the score, the tablet plane is beveled inward.

Excipients : lactose monohydrate – 99.77 mg, corn starch – 22.5 mg, povidone K30 – 3 mg, glycine hydrochloride – 3 mg, alginic acid – 13 mg, colloidal silicon dioxide – 1.5 mg, magnesium stearate – 1.2 mg, iron oxide red dye (E172) – 0.03 mg.

10 pcs. – blisters (3) – cardboard packs.

Tablets from light pink with marbling to pink with an orange tint with marbling, round, with beveled edges, with a smooth surface and a score on one side; on the side with the score, the tablet plane is beveled inward.

Excipients : lactose monohydrate – 99.77 mg, corn starch – 22.5 mg, povidone K30 – 3 mg, glycine hydrochloride – 3 mg, alginic acid – 13 mg, colloidal silicon dioxide – 1.5 mg, magnesium stearate – 1.2 mg, iron oxide red dye (E172) – 0.03 mg.

10 pcs. – blisters (3) – cardboard packs.

Clinical-Pharmacological Group

ACE inhibitor

Pharmacotherapeutic Group

ACE blocker

Pharmacological Action

Inhibitor of ACE, an enzyme that catalyzes the conversion of angiotensin I to angiotensin II. Angiotensin II has a powerful vasoconstrictive effect, enhances potassium excretion and delays sodium excretion.

Spirapril has antihypertensive, vasodilatory, cardioprotective and natriuretic effects, primarily by affecting the renin-angiotensin-aldosterone system; it also promotes the release of biologically active substances that have natriuretic and vasodilatory effects (prostaglandins E1 and E2, endothelial relaxing factor, atrial natriuretic factor) and reduces the formation of arginine-vasopressin and endothelin-1, which have vasoconstrictive properties.

The effect of the drug develops within 1 hour after administration, reaches a maximum after 4-8 hours and lasts about 24 hours.

Pharmacokinetics

Absorption

After oral administration of the drug, absorption from the gastrointestinal tract is 45%. The absolute bioavailability of spirapril is approximately 50%, and that of spiraprilat is 70%. C_max in blood plasma for spirapril is reached after 45-90 minutes, for spiraprilat – after 2-3 hours.

Distribution

Binding to plasma proteins of spirapril and its active metabolite is 90%.

Metabolism

It is biotransformed in the liver to form an active metabolite, spiraprilat.

Excretion

It is excreted in the urine (40%) and feces (51%) unchanged and in the form of metabolites. T_1/2 is 2 hours for the first excretion phase and 40 hours for the second phase.

Indications

• Arterial hypertension;
• Chronic heart failure (as part of combination therapy).

ICD codes

Dosage Regimen

The drug is taken orally, regardless of meals, with a sufficient amount of liquid, without chewing.

For arterial hypertension and chronic heart failure, the initial daily dose of the drug is 3 mg (1/2 tab.). If necessary, the daily dose can be increased to 6 mg (1 tab.). The maintenance dose is, on average, 6 mg (1 tab.) per day. The maximum daily dose is 6 mg.

The duration of the treatment course is determined by the doctor individually.

For patients with impaired renal function ( CC 10-30 ml/min), the recommended daily dose is 3 mg (1/2 tab.), taken in the morning. Treatment is started only under the condition of careful medical supervision of the patient. Depending on the indicators of renal function, the daily dose of the drug can be increased to a maximum of 6 mg (1 tab.) in individual justified cases, taken in the morning.

In patients with moderate renal impairment (CC 30-60 ml/min), impaired liver function, as well as in elderly patients, no dose reduction is required.

Adverse Reactions

From the cardiovascular system : decreased blood pressure, orthostatic hypotension; rarely – fainting; in isolated cases – tachycardia, arrhythmias, angina pectoris, myocardial infarction, increased manifestations of peripheral circulatory failure, exacerbation of Raynaud’s disease.

From the urinary system hypercreatininemia, development or worsening of chronic renal failure, proteinuria.

From the central and peripheral nervous system cerebral stroke, dizziness, headache, weakness; when used in high doses – insomnia, anxiety, depression, confusion, paresthesia, sleep disorders, balance disorders.

From the senses : vestibular disorders, hearing and vision disorders, tinnitus, taste disturbances or temporary loss of taste.

From the digestive system : nausea, diarrhea, cholestatic jaundice, dyspepsia, constipation, decreased appetite, stomatitis, glossitis, dry mouth, increased activity of liver transaminases, hyperbilirubinemia; in isolated cases – intestinal obstruction, impaired liver function, hepatitis, pancreatitis and progressive liver necrosis (up to death).

From the respiratory system dry cough, pulmonary infiltrates, bronchospasm, shortness of breath, rhinitis, rhinorrhea, sinusitis, pharyngitis, dysphonia.

Allergic reactions : skin rash, itching, urticaria, photosensitivity, angioedema of the face, extremities, lips, tongue, glottis and/or larynx, multiforme erythema, exfoliative dermatitis, malignant exudative erythema (Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell’s syndrome); in isolated cases – angioedema of the intestine.

From the hematopoietic system anemia, leukopenia, thrombocytopenia; rarely – eosinophilia; in isolated cases – agranulocytosis, pancytopenia, hemolysis.

From metabolism increased urea content, hyperkalemia, hyponatremia.

Other : alopecia, onycholysis, decreased potency; in isolated cases – increased titer of antinuclear antibodies.

Contraindications

• History of angioedema while taking ACE inhibitors;
• Hereditary or idiopathic angioedema;
• Pregnancy;
• Lactation period (breastfeeding);
• Age under 18 years (efficacy and safety have not been established);
• Hypersensitivity to the components of the drug.

With caution, the drug should be prescribed for bilateral renal artery stenosis, stenosis of the artery of a single kidney, severe renal impairment (CC < 10 ml/min), condition after kidney transplantation, stenosis of the aortic or mitral valve, hypertrophic obstructive cardiomyopathy, primary hyperaldosteronism, systemic connective tissue diseases (for example, SLE, scleroderma), impaired liver function, cerebro- and cardiovascular diseases (including cerebral circulatory insufficiency, coronary artery disease, coronary insufficiency), bone marrow hematopoiesis depression, diabetes mellitus, hyperkalemia, adherence to a sodium-restricted diet, in conditions accompanied by a decrease in circulating blood volume (including diarrhea, vomiting), as well as in elderly patients.

Use in Pregnancy and Lactation

Quadropril^® is contraindicated for use during pregnancy.

If it is necessary to use Quadropril^® during lactation, breastfeeding should be discontinued.

If pregnancy occurs during treatment with Quadropril^®, therapy should be discontinued, because taking Quadropril^® may cause intrauterine fetal damage (impaired kidney development, decreased blood pressure in the fetus and newborns, impaired renal function, hyperkalemia, skull hypoplasia, oligohydramnios, limb contractures, skull deformation, lung hypoplasia).

Use in Hepatic Impairment

With caution, Quadropril^® should be used for impaired liver function.

Use in Renal Impairment

With caution, Quadropril^® should be used for severe renal impairment (CC 10-30 ml/min). The drug is contraindicated for use with CC less than 10 ml/min.

Pediatric Use

The efficacy and safety of the drug in children under 18 years of age have not been established.

Geriatric Use

In elderly patients, no dose reduction is required.

Special Precautions

Arterial hypotension that occurs after taking the first dose is not a contraindication for further use of Quadropril^® (after normalization of blood pressure, subsequent regular administration does not lead to arterial hypotension).

In patients with renovascular hypertension, it is necessary to systematically monitor the content of creatinine and urea in the plasma.

In patients with autoimmune diseases, regular monitoring of the leukocyte count in the blood is necessary.

Prescription against the background of hyperkalemia should be carried out under the control of the concentration of potassium in the blood plasma.

When performing surgical interventions using general anesthesia in patients taking Quadropril^®, a pronounced decrease in blood pressure is possible. Before general anesthesia, it is necessary to warn the anesthesiologist about the use of ACE inhibitors.

During treatment with Quadropril^®, membranes containing polyacrylonitrile-metallylsulfonate (for example, AN69) should not be used for hemodialysis or hemofiltration, as there is a danger of hypersensitivity reactions up to the development of shock, life-threatening to the patient. If emergency dialysis or hemofiltration is necessary, before these procedures, the patient is either prescribed another antihypertensive drug (not an ACE inhibitor), or another dialysis membrane is used.

During plasmapheresis with dextran sulfate with concomitant therapy with an ACE inhibitor, life-threatening hypersensitivity reactions may occur.

During desensitizing therapy aimed at eliminating symptoms caused by insect venom (bee or wasp stings), against the background of taking an ACE inhibitor, anaphylactic reactions may develop, sometimes life-threatening to the patient (decreased blood pressure, shortness of breath, vomiting, allergic skin rashes).

Treatment is carried out under constant medical supervision.

In patients with a reduced circulating blood volume in the body (caused, for example, by vomiting, diarrhea, taking diuretics), weakened heart contractility or malignant arterial hypertension, a sharp drop in blood pressure may be noted at the beginning of treatment with Quadropril^®. If possible, before starting treatment with Quadropril^®, the deficiency of circulating blood volume in the body should be replenished or the ongoing therapy with diuretics should be limited and, if necessary, they should be discontinued.

To avoid an unpredictable sharp drop in blood pressure after taking the first dose, as well as after increasing the dose of diuretics and/or increasing the dose of Quadropril^®, these patients are placed under medical supervision for at least 6 hours.

Since in rare cases, when taking ACE inhibitors, angioedema of the face, extremities, lips, tongue, larynx or pharynx is noted, this side reaction may also occur when taking Quadropril^®. In this case, treatment with Quadropril^® should be stopped immediately and the patient’s condition should be monitored until the edema completely disappears. Even in the case of tongue edema without respiratory impairment, prolonged observation of the patient’s condition and emergency measures may be required, since in very rare cases, edema of the tongue and larynx has been fatal.

In case of tissue edema involving the larynx, pharynx and/or tongue, epinephrine should be urgently administered subcutaneously at a dose of 0.3-0.5 mg or slowly intravenously at a dose of 0.1 mg under ECG and blood pressure control, then corticosteroids are prescribed. After this, intravenous administration of antihistamines (histamine H₁-receptor blockers) is recommended.

In patients with malignant arterial hypertension or heart failure, therapy with Quadropril^® is started in a hospital.

During treatment, it is necessary to refrain from taking ethanol.

Effect on ability to drive vehicles and mechanisms

During the treatment period, it is necessary to refrain from engaging in potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

Symptoms pronounced decrease in blood pressure, bradycardia, collapse, shock, water-electrolyte balance disorders, acute renal failure.

Treatment symptomatic (gastric lavage, administration of adsorbents). In severe cases – hospitalization and maintenance of vital body functions in a hospital setting.

To remove the drug from the body, a session of hemodialysis can be performed. For arterial hypotension, first of all, the circulating blood volume is replenished by intravenous infusion of saline. If necessary, catecholamines are additionally administered intravenously. For severe bradycardia that is not relieved with medication, an artificial pacemaker is implanted. Control of the concentration of electrolytes and creatinine in the blood is necessary.

Drug Interactions

Antihypertensive drugs (especially in combination with diuretics), hypnotics, and general anesthetics enhance the hypotensive effect of Quadropril^®.

NSAIDs (for example, acetylsalicylic acid, indomethacin), including COX-2 inhibitors, may weaken the hypotensive effect of Quadropril^®.

With simultaneous use of Quadropril^® with potassium preparations, potassium-sparing diuretics (for example, spironolactone, amiloride, triamterene), as well as heparin, the risk of hyperkalemia increases.

Quadropril^® when used simultaneously with lithium salts causes an increase in the concentration of lithium in the blood plasma (systematic monitoring of the concentration of lithium in the blood serum is necessary).

With the combined use of Quadropril^® with allopurinol, procainamide, as well as with drugs that suppress the body’s defense reactions (cytostatic, immunosuppressive drugs, systemic corticosteroids), the risk of developing leukopenia increases.

Quadropril^® enhances the hypoglycemic effect of insulin, oral hypoglycemic agents (biguanides, sulfonylurea derivatives).

With simultaneous use with estrogens or table salt, the antihypertensive effect of Quadropril^® is weakened.

Simultaneous administration of Quadropril^® and ethanol leads to an enhancement of the effect of ethanol.

Storage Conditions

List B. The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.