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Militian Inessa Mesropovna tarafından tıbbi olarak gözden geçirilmiştir, Eczane Son güncelleme: 06.04.2022
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Trandolapril ve Verapamil Hidroklorür, hipertansiyon tedavisi için endikedir.
Bu sabit kombinasyon ilacı, hipertansiyonun ilk tedavisi için endike değildir (bkz. DOZAJ VE YÖNETİM).
Trandolapril ve Verapamil Hidroklorür kullanılırken, anjiyotensin dönüştürücü bir enzim inhibitörü olan kaptopril, özellikle böbrek yetmezliği veya kollajen vasküler hastalığı olan hastalarda agranülositoza neden olduğu ve mevcut verilerin trandolaprilin olmadığını göstermek için yetersiz olduğu dikkate alınmalıdır. benzer risk (bkz UYARILAR -Nötropeni / Agranülositoz).
Hipertansiyon için önerilen normal dozaj trandolapril aralığı, tek bir dozda veya iki bölünmüş dozda günde 1 ila 4 mg'dır. Hipertansiyon için önerilen olağan Isoptin-SR dozaj aralığı, tek bir dozda veya iki bölünmüş dozda günde 120 ila 480 mg'dır.
Tehlikeler (bkz UYARILAR) trandolapril genellikle dozdan bağımsızdır; verapamil olanlar doza bağlı fenomenlerin (öncelikle baş dönmesi, AV bloğu, kabızlık) ve dozdan bağımsız fenomenlerin bir karışımıdır, bunlardan ilki çok daha yaygındır. Trandolapril ve verapamil'in herhangi bir kombinasyonu ile tedavi, her iki dozdan bağımsız tehlike seti ile ilişkili olacaktır. Verapamilin doza bağlı yan etkilerinin, trandolapril ilavesiyle veya tam tersi ile azaldığı gösterilmemiştir.
Nadiren, trandolaprilin dozdan bağımsız tehlikeleri ciddidir. Dozdan bağımsız tehlikeleri en aza indirmek için, Trandolapril ve Verapamil Hidroklorür ile tedaviye ancak bir hastadan sonra başlamak genellikle uygundur (a) bir veya diğer monoterapi ile ilgili maksimum önerilen dozda ve en kısa doz aralığında istenen antihipertansif etkiyi elde edemedi, veya (b) doz sınırlayıcı yan etkiler nedeniyle bir veya diğer monoterapinin dozu daha da arttırılamaz.
Trandolapril ve Verapamil Hidroklorür ile yapılan klinik çalışmalar günde sadece bir kez dozları araştırmıştır. Günde iki kez uygulanan 240 mg İzoptin-SR dozuna günde bir kez 4 mg trandolapril eklenmesinin antihipertansif etkisi ve / veya yan etkileri araştırılmamıştır veya 180 mg'dan az ekleme etkisi yoktur. Günde iki kez uygulanan 2 mg trandolapril'e İzoptin-SR değerlendirildi. Günde bir kez İzoptin-SR 120 ila 240 mg ve günde bir kez 0.5 ila 8 mg trandolapril doz aralığında, kombinasyonun etkileri her iki bileşenin artan dozlarıyla artar.
Değiştirme Terapisi
Kolaylık sağlamak için, günde bir kez uygulanan ayrı tabletlerde trandolapril (8 mg'a kadar) ve verapamil (240 mg'a kadar) alan hastalar, bunun yerine aynı bileşen dozlarını içeren Trandolapril ve Verapamil Hidroklorür tabletlerini almak isteyebilirler.
Trandolapril ve Verapamil Hidroklorür gıda ile uygulanmalıdır.
Trandolapril ve Verapamil Hidroklorür, herhangi bir ACE inhibitörü veya verapamil'e aşırı duyarlı olan hastalarda kontrendikedir.
Verapamil bileşeni nedeniyle, Trandolapril ve Verapamil Hidroklorür kontrendikedir:
- Şiddetli sol ventrikül disfonksiyonu (bkz UYARILAR).
- Hipotansiyon (sistolik basınç 90 mmHg'den az) veya kardiyojenik şok.
- Hasta sinüs sendromu (işleyen yapay ventrikül kalp pili olan hastalar hariç).
- İkinci veya üçüncü derece AV bloğu (işleyen yapay ventrikül kalp pili olan hastalar hariç).
- Atriyal çarpıntı veya atriyal fibrilasyon ve aksesuar bypass sistemi olan hastalar (ör. Wolff- Parkinson-White, Lown-Ganong-Levine sendromları) (bkz UYARILAR).
Trandolapril bileşeni nedeniyle, Trandolapril ve Verapamil Hidroklorür, anjiyotensin dönüştürücü enzim (ACE) inhibitörü ile önceki tedaviye bağlı anjiyoödem öyküsü olan hastalarda kontrendikedir.
Diyabetli hastalarda aliskireni Trandolapril ve Verapamil Hidroklorür ile birlikte uygulamayın (bkz İLAÇ ETKİLEŞİMLERİ).
Trandolapril ve Verapamil Hidroklorür, neprilizin inhibitörü (örn., sakubitril). Bir neprilizin inhibitörü olan sakubitril / valsartan'a geçtikten sonra 36 saat içinde Trandolapril ve Verapamil Hidroklorür uygulamayın (bkz UYARILAR).
WARNINGS
Heart Failure
Verapamil Component
Verapamil has a negative inotropic effect which, in most patients, is compensated by its afterload reduction (decreased systemic vascular resistance) properties without a net impairment of ventricular performance. In clinical experience with 4,954 patients, 87 (1.8%) developed congestive heart failure or pulmonary edema. Verapamil should be avoided in patients with severe left ventricular dysfunction (e.g., ejection fraction less than 30%, pulmonary wedge pressure above 20 mmHg, or severe symptoms of cardiac failure) and in patients with any degree of ventricular dysfunction if they are receiving a beta adrenergic blocker (see DRUG INTERACTIONS). Patients with milder ventricular dysfunction should, if possible, be controlled with optimum doses of digitalis and/or diuretics before verapamil treatment (Note interactions with digoxin under: PRECAUTIONS).
Trandolapril Component
Trandolapril, as an ACE inhibitor, may cause excessive hypotension in patients with congestive heart failure (see WARNINGS -Hypotension).
Hypotension
Verapamil Component
Occasionally, the pharmacologic action of verapamil may produce a decrease in blood pressure below normal levels which may result in dizziness or symptomatic hypotension.
Trandolapril Component
Trandolapril can cause symptomatic hypotension. Like other ACE inhibitors, trandolapril has only rarely been associated with symptomatic hypotension in uncomplicated hypertensive patients. Symptomatic hypotension is most likely to occur in patients who are salt-or volume-depleted as a result of prolonged treatment with diuretics, dietary salt restriction, dialysis, diarrhea, or vomiting. Volume and/or salt depletion should be corrected before initiating treatment with trandolapril (see PRECAUTIONS and DRUG INTERACTIONS and ADVERSE REACTIONS).
In controlled studies, hypotension was observed in 0.6% of patients receiving any combination of trandolapril and verapamil HCl ER.
In patients with concomitant congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension, which may be associated with oliguria or azotemia, and, rarely, with acute renal failure and death (see DOSAGE AND ADMINISTRATION).
If symptomatic hypotension occurs, the patient should be placed in the supine position and, if necessary, normal saline may be administered intravenously. A transient hypotensive response is not a contraindication to further doses; however, lower doses of verapamil HCl ER and/or trandolapril or reduced concomitant diuretic therapy should be considered.
Elevated Liver Enzymes/Hepatic Failure
Verapamil Component
Elevations of transaminases with and without concomitant elevations in alkaline phosphatase and bilirubin have been reported. Such elevations have sometimes been transient and may disappear even in the face of continued verapamil treatment. Several cases of hepatocellular injury related to verapamil have been proven by rechallenge; half of these had clinical symptoms (malaise, fever, and/or right upper quadrant pain) in addition to elevations of SGOT, SGPT, and alkaline phosphatase.
Trandolapril Component
ACE inhibitors rarely have been associated with a syndrome of cholestatic jaundice, fulminant hepatic necrosis, and death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice should discontinue the ACE inhibitor and receive appropriate medical follow-up.
Liver abnormalities were noted in 3.2% of patients taking any of several combinations of trandolapril/verapamil doses. Periodic monitoring of liver function in patients taking Trandolapril And Verapamil Hydrochloride is therefore prudent.
Accessory Bypass Tract (Wolff-Parkinson-White Or Lown-Ganong-Levine Syndromes)
Verapamil Component
Some patients with paroxysmal and/or chronic atrial fibrillation or atrial flutter and a coexisting accessory AV pathway have developed increased antegrade conduction across the accessory pathway bypassing the AV node, producing a very rapid ventricular response or ventricular fibrillation after receiving intravenous verapamil (or digitalis). Although a risk of this occurring with oral verapamil has not been established, such patients receiving oral verapamil may be at risk and its use in these patients is contraindicated (see CONTRAINDICATIONS).
Treatment is usually DC-cardioversion. Cardioversion has been used safely and effectively after oral verapamil.
Atrioventricular Block
Verapamil Component
The effect of verapamil on AV conduction and the SA node may lead to asymptomatic first-degree AV block and transient bradycardia, sometimes accompanied by nodal escape rhythms. PR interval prolongation is correlated with verapamil plasma concentrations, especially during the early titration phases of therapy. Higher degrees of AV block, however, were infrequently (0.8%) observed. Marked first-degree block or progressive development to second-or third-degree AV block requires a reduction in dosage or, in rare instances, discontinuation of verapamil HCl and institution of appropriate therapy depending upon the clinical situation.
Patients With Hypertrophic Cardiomyopathy (IHSS)
Verapamil Component
In 120 patients with hypertrophic cardiomyopathy (most of them refractory or intolerant to propranolol) who received therapy with verapamil at doses up to 720 mg/day, a variety of serious adverse effects were seen. Three patients died in pulmonary edema; all had severe left ventricular outflow obstruction and a past history of left ventricular dysfunction. Eight other patients had pulmonary edema and/or severe hypotension; abnormally high (over 20 mmHg) capillary wedge pressure and a marked left ventricular outflow obstruction were present in most of these patients. Sinus bradycardia occurred in 11% of the patients, second-degree AV block in 4% and sinus arrest in 2%. It must be appreciated that this group of patients had a serious disease with a high mortality rate. Most adverse effects responded well to dose reduction and only rarely did verapamil have to be discontinued.
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 trandolapril may be subject to a variety of adverse reactions, some of them serious.
Angioedema
Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients treated with ACE inhibitors including trandolapril. Symptoms suggestive of angioedema or facial edema occurred in 0.13% of trandolapril-treated patients. Two of the four cases were life-threatening and resolved without treatment or with medication (corticosteroids). Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of the face, tongue or glottis occurs, treatment with Trandolapril And Verapamil Hydrochloride should be discontinued immediately, the patient treated in accordance with accepted medical care and carefully observed until the swelling disappears. In instances where swelling is confined to the face and lips, the condition generally resolves without treatment; antihistamines may be useful in relieving symptoms.
Where there is involvement of the tongue, glottis, or larynx, likely to cause airway obstruction, emergency therapy, including but not limited to subcutaneous epinephrine solution 1:1,000 (0.3 to 0.5 mL) should be promptly administered (see PRECAUTIONS and ADVERSE REACTIONS).
Patients receiving coadministration of an ACE inhibitor with an mTOR (mammalian target of rapamycin) inhibitor (e.g., temsirolimus, sirolimus, everolimus) or a neprilysin inhibitor (e.g., sacubitril) may be at increased risk for angioedema.
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 did not occur when ACE inhibitors were temporarily withheld, but they reappeared when the ACE inhibitors were inadvertently readministered.
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.
Neutropenia/Agranulocytosis
Trandolapril Component
Another ACE inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression rarely in patients with uncomplicated hypertension, but more frequently in patients with renal impairment, especially if they also have a collagen-vascular disease such as systemic lupus erythematosus or scleroderma. Available data from clinical trials of trandolapril or Trandolapril And Verapamil Hydrochloride are insufficient to show that trandolapril does not cause agranulocytosis at similar rates. As with other ACE inhibitors, periodic monitoring of white blood cell counts in patients with collagen-vascular disease and/or renal disease should be considered.
Fetal Toxicity
Pregnancy Category D
Trandolapril Component
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 Trandolapril And Verapamil Hydrochloride as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the reninangiotensin 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 Trandolapril And Verapamil Hydrochloride, unless it is considered lifesaving 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 Trandolapril And Verapamil Hydrochloride for hypotension, oliguria, and hyperkalemia (see PRECAUTIONS -Pediatric Use).
Doses of 0.8 mg/kg/day (9.4 mg/m2/day in rabbits, 1000 mg/kg/day (7000 mg/m2/day) in rats, and 25 mg/kg/day (295 mg/m2/day) in cynomolgus monkeys did not produce teratogenic effects. These doses represent 10 and 3 times (rabbits), 1250 and 2564 times (rats), and 312 and 108 times (monkeys) the maximum projected human dose of 4 mg based on body-weight and bodysurface-area, respectively assuming a 50 kg woman.
Trandolapril in doses of 0.8 mg/kg/day in rabbits, 100.0 mg/kg/day in rats, and 25 mg/kg/day in cynomolgus monkeys (10, 1250, and 312 times the maximum projected human dose, respectively, assuming a 50 kg woman) did not produce teratogenic effects.
PRECAUTIONS
Use In Patients With Impaired Hepatic Function
Trandolapril And Verapamil Hydrochloride has not been evaluated in subjects with impaired hepatic function.
Verapamil Component
Since verapamil is highly metabolized by the liver, it should be administered cautiously to patients with impaired hepatic function. Severe liver dysfunction prolongs the elimination half-life of immediate release verapamil to about 14 to 16 hours; hence, approximately 30% of the dose given to patients with normal liver function should be administered to these patients.
Careful monitoring for abnormal prolongation of the PR interval or other signs of excessive pharmacologic effects (see OVERDOSE) should be carried out.
Trandolapril Component
Trandolapril and trandolaprilat concentrations increase in patients with impaired liver function.
Use In Patients With Impaired Renal Function
Trandolapril And Verapamil Hydrochloride has not been evaluated in patients with impaired renal function.
Verapamil Component
About 70% of an administered dose of verapamil is excreted as metabolites in the urine. Verapamil is not removed by hemodialysis. Until further data are available, verapamil should be administered cautiously to patients with impaired renal function. These patients should be carefully monitored for abnormal prolongation of the PR interval or other signs of overdosage (see OVERDOSE).
Trandolapril Component
As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with ACE inhibitors, including trandolapril, 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 have been observed in some patients following ACE inhibitor therapy. These increases were almost always reversible upon discontinuation of the ACE inhibitor 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 ACE inhibitors have been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of any diuretic and/or the ACE inhibitor may be required.
Evaluation of hypertensive patients should always include assessment of renal function (see DOSAGE AND ADMINISTRATION).
Use In Patients With Attenuated (Decreased) Neuromuscular Transmission
Verapamil Component
It has been reported that verapamil decreases neuromuscular transmission in patients with Duchenne’s muscular dystrophy, and that verapamil prolongs recovery from the neuromuscular blocking agent vecuronium. It may be necessary to decrease the dosage of verapamil when it is administered to patients with attenuated neuromuscular transmission (see PRECAUTIONS - Surgery/Anesthesia).
Hyperkalemia And Potassium-Sparing Diuretics
Trandolapril Component
In clinical trials, hyperkalemia (serum potassium > 6.00 mEq/L) occurred in approximately 0.4 percent of hypertensive patients receiving trandolapril and in 0.8% of patients receiving a dose of trandolapril (0.5-8 mg) in combination with a dose of verapamil SR (120-240 mg). In most cases, elevated serum potassium levels were isolated values, which resolved despite continued therapy. None of these patients were discontinued from the trials because of hyperkalemia. 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 trandolapril (see PRECAUTIONS and DRUG INTERACTIONS).
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. In controlled trials of trandolapril, cough was present in 2% of trandolapril patients and 0% of patients given placebo. There was no evidence of a relationship to dose.
Surgery/Anesthesia
Trandolapril Component
In patients undergoing major surgery or during anesthesia with agents that produce hypotension, trandolapril will 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 (see PRECAUTIONS -Use In Patients With Attenuated (Decreased) Neuromuscular Transmission).
Ivabradine
Concurrent use of verapamil increases exposure to ivabradine and may exacerbate bradycardia and conduction disturbances. Avoid co-administration of verapamil and ivabradine.
Digitalis
Clinical use of verapamil in digitalized patients has shown the combination to be well tolerated if digoxin doses are properly adjusted. Chronic verapamil treatment can increase serum digoxin levels by 50 to 75% during the first week of therapy, and this can result in digoxin toxicity. In patients with hepatic cirrhosis, the influence of verapamil on digoxin kinetics is magnified. Verapamil may reduce total body clearance and extrarenal clearance of digitoxin by 27% and 29%, respectively. Maintenance digoxin doses should be reduced when verapamil is administered, and the patient should be carefully monitored to avoid over-or under-digitalization. Whenever overdigitalization is suspected, the daily dose of digoxin should be reduced or temporarily discontinued. Upon discontinuation of any verapamil-containing regime including Trandolapril And Verapamil Hydrochloride (trandolapril/verapamil hydrochloride ER), the patient should be reassessed to avoid underdigitalization. No clinically significant pharmacokinetic interaction has been found between trandolapril (or its metabolites) and digoxin.
Lithium
Verapamil Component
Increased sensitivity to the effects of lithium (neurotoxicity) has been reported during concomitant verapamil-lithium therapy with either no change or an increase in serum lithium levels. Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. Trandolapril And Verapamil Hydrochloride and lithium should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased.
Clarithromycin
Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent clarithromycin.
Erythromycin
Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent erythromycin ethylsuccinate.
Cimetidine
The interaction between cimetidine and chronically administered verapamil has not been studied. Variable results on clearance have been obtained in acute studies of healthy volunteers; clearance of verapamil was either reduced or unchanged. No clinically significant pharmacokinetic interaction has been found between trandolapril (or its metabolites) and cimetidine.
Antiarrhythmic Agents
Verapamil Component
Disopyramide Phosphate
Data on possible interactions between verapamil and disopyramide phosphate are not available. Therefore, disopyramide should not be administered within 48 hours before or 24 hours after verapamil administration.
Flecainide
A study of healthy volunteers showed that the concomitant administration of flecainide and verapamil may have additive effects on myocardial contractility, AV conduction, and repolarization. Concomitant therapy with flecainide and verapamil may result in additive negative inotropic effect and prolongation of atrioventricular conduction.
Quinidine
The electrophysiological effects of quinidine and verapamil on AV conduction were studied in 8 patients. Verapamil significantly counteracted the effects of quinidine on AV conduction. There has been a report of increased quinidine levels during verapamil therapy.
Antihypertensive Agents
Concomitant use of Trandolapril And Verapamil Hydrochloride with other antihypertensive agents including diuretics, vasodilators, beta-adrenergic blockers, and alpha-antagonists may result in additive hypotensive effects. There are reports that verapamil may result in higher concentrations of the alpha-agonists prazosin and terazosin.
Dual Blockade Of The Renin-Angiotensin System (RAS)
Trandolapril Component
Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function and electrolytes in patients on Trandolapril And Verapamil Hydrochloride and other agents that affect the RAS.
Do not co-administer aliskiren with Trandolapril And Verapamil Hydrochloride in patients with diabetes. Avoid use of aliskiren with Trandolapril And Verapamil Hydrochloride in patients with renal impairment (GFR <60 ml/min).
Beta Blockers
Verapamil Component
Concomitant therapy with beta-adrenergic blockers and verapamil may result in additive negative effects on heart rate, atrioventricular conduction, and/or cardiac contractility. Drug interaction studies have indicated that the maximum concentrations of metoprolol and propanolol are increased after the administration of verapamil. The use of verapamil in combination with a beta-adrenergic blocker should be used only with caution, and close monitoring.
Asymptomatic bradycardia (36 beats/min) with a wandering atrial pacemaker has been observed in a patient receiving concomitant timolol (a beta-adrenergic blocker) eyedrops and oral verapamil.
Concomitant Diuretic Therapy
Trandolapril Component
As with other ACE inhibitors, patients on diuretics, especially those on recently instituted diuretic therapy, may occasionally experience an excessive reduction of blood pressure afterinitiation of therapy with Trandolapril And Verapamil Hydrochloride. The possibility of exacerbation of hypotensive effects with Trandolapril And Verapamil Hydrochloride may be minimized by either discontinuing the diuretic or cautiously increasing salt intake prior to initiation of treatment with Trandolapril And Verapamil Hydrochloride. If it is not possible to discontinue the diuretic, the starting dose of Trandolapril And Verapamil Hydrochloride should be reduced (see DOSAGE AND ADMINISTRATION). No clinically significant pharmacokinetic interaction has been found between trandolapril (or its metabolites) and furosemide.
Agents Increasing Serum Potassium
Trandolapril Component
Trandolapril can attenuate potassium loss caused by thiazide diuretics and increase serum potassium when used alone. Use of potassium-sparing diuretics (spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes concomitantly with ACE inhibitors can increase the risk of hyperkalemia. If concomitant use of such agents is indicated, they should be used with caution and with appropriate monitoring of serum potassium (see PRECAUTIONS).
HMG-CoA Reductase Inhibitors (“Statins”)
Verapamil component
The use of HMG-CoA reductase inhibitors that are CYP3A4 substrates in combination with verapamil has been associated with reports of myopathy/rhabdomyolysis.
Co-administration of multiple doses of 10 mg of verapamil with 80 mg simvastatin resulted in exposure to simvastatin 2.5-fold that following simvastatin alone. Limit the dose of simvastatin in patients on verapamil to 10 mg daily. Limit the daily dose of lovastatin to 40 mg. Lower starting and maintenance doses of other CYP3A4 substrates (e.g., atorvastatin) may be required as verapamil may increase the plasma concentration of these drugs.
Non-Steroidal Anti-Inflammatory Agents Including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors)
Trandolapril Component
In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including trandolapril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving trandolapril and NSAID therapy.
The antihypertensive effect of ACE inhibitors, including trandolapril may be attenuated by NSAIDs.
Neprilysin Inhibitor
Trandolapril Component
Patients taking concomitant neprilysin inhibitors (e.g., sacubitril) may be at increased risk for angioedema (see WARNINGS).
Other (Verapamil Component)
Nitrates
Verapamil has been given concomitantly with short-and long-acting nitrates without any undesirable drug interactions. The pharmacologic profile of both drugs and the clinical experience suggest beneficial interactions.
Carbamazepine
Verapamil may increase carbamazepine concentrations during combined therapy. This may produce carbamazepine side effects such as diplopia, headache, ataxia, or dizziness.
Anti-Infective Agents
Therapy with rifampin may markedly reduce oral verapamil bioavailability. There have been reports that erythromycin and telithromycin may increase concentrations of verapamil.
Barbiturates
Phenobarbital therapy may increase verapamil clearance.
Immunosuppressive Agents
Verapamil therapy may increase serum levels of cyclosporin, sirolimus and tacrolimus.
Theophylline
Verapamil therapy may inhibit the clearance and increase the plasma levels of theophylline.
Tranquilizers/ Anti-Depressants
Due to metabolism via the CYP enzyme system, there have been reports that verapamil may increase the concentrations of buspirone, midazolam, almotriptan and imipramine.
Colchicine
Colchicine is a substrate for both CYP3A and the efflux transporter, P-gp. Verapamil is known to inhibit CYP3A and P-gp. When verapamil and colchicine are administered together, the potential inhibition of P-gp and/or CYP3A by verapamil may lead to increased exposure to colchicine (see PRECAUTIONS and DRUG INTERACTIONS).
Dabigatran
Verapamil, a P-gp inhibitor, increases exposure to dabigatran (a thrombin inhibitor) when administered concomitantly; however, no dose adjustment of dabigatran is required when administered with verapamil.
Other
Concentrations of verapamil may be increased by the concomitant administration of protease inhibitors such as ritonavir, and reduced by the concomitant administration of sulfinpyrazone, or St John’s Wort.
Concentrations of doxorubicin may be increased by the administration of verapamil.
There have been reports that verapamil may elevate the concentrations of the oral anti-diabetic glyburide.
Inhalation Anesthetics
Animal experiments have shown that inhalation anesthetics depress cardiovascular activity by decreasing the inward movement of calcium ions. When used concomitantly, inhalation anesthetics and calcium antagonists, such as verapamil, should be titrated carefully to avoid excessive cardiovascular depression.
Neuromuscular Blocking Agents
Clinical data and animal studies suggest that verapamil may potentiate the activity of neuromuscular blocking agents (curare-like and depolarizing). It may be necessary to decrease the dose of verapamil and/or the dose of the neuromuscular blocking agent when the drugs are used concomitantly.
Gold
Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including Trandolapril And Verapamil Hydrochloride.
Other (Trandolapril Component)
No clinically significant pharmacokinetic interaction has been found between trandolapril (or its metabolites) and nifedipine.
The anticoagulant effect of warfarin was not significantly changed by trandolapril.
Mammalian Target Of Rapamycin (mTOR) Inhibitors
Patients taking concomitant mTOR inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy may be at increased risk for angioedema (see WARNINGS -Angioedema).
Anti-Diabetic Agents
The concomitant use of ACE inhibitors such as trandolapril with antidiabetic medications (insulin or oral hypoglycemic agents) may result in increased blood glucose lowering effects.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Verapamil Component
An 18-month toxicity study in rats, at a low multiple (6 fold) of the maximum recommended human dose, and not the maximum tolerated dose, did not suggest a tumorigenic potential. There was no evidence of a carcinogenic potential of verapamil administered in the diet of rats for two years at doses of 10, 35, and 120 mg/kg per day or approximately 1x, 3.5x, and 12x, respectively, the maximum recommended human daily dose (480 mg per day or 9.6 mg/kg/day).
Verapamil was not mutagenic in the Ames test in 5 test strains at 3 mg per plate, with or without metabolic activation.
Studies in female rats at daily dietary doses up to 5.5 times (55 mg/kg/day) the maximum recommended human dose did not show impaired fertility. Effects on male fertility have not been determined.
Trandolapril Component
Long-term studies were conducted with oral trandolapril administered by gavage to mice (78 weeks) and rats (104 and 106 weeks). No evidence of carcinogenic potential was seen in mice dosed up to 25 mg/kg/day (85 mg/m2/day) or rats dosed up to 8 mg/kg/day (60 mg/m2/day). These doses are 313 and 32 times (mice), and 100 and 23 times (rats) the maximum recommended human daily dose (MRHDD) of 4 mg based on body-weight and body-surfacearea, respectively assuming a 50 kg individual. The genotoxic potential of trandolapril was evaluated in the microbial mutagenicity (Ames) test, the point mutation and chromosome aberration assays in Chinese hamster V79 cells, and the micronucleus test in mice. There was no evidence of mutagenic or clastogenic potential in these in vitro and in vivo assays.
Reproduction studies in rats did not show any impairment of fertility at doses up to 100 mg/kg/day (710 mg/m2/day) of trandolapril, or 1250 and 260 times the MRHDD on the basis of body-weight and body-surface-area, respectively.
Pregnancy
Female patients of childbearing age should be told about the consequences of exposure to Trandolapril And Verapamil Hydrochloride during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible.
Nursing Mothers
Verapamil is excreted in human milk. Radiolabeled trandolapril or its metabolites are secreted in rat milk. Trandolapril And Verapamil Hydrochloride should not be administered to nursing mothers.
Geriatric Use
In placebo-controlled studies, where 23% of patients recei
Trandolapril ve Verapamil Hidroklorür 1.957'den fazla hasta ve hastada değerlendirilmiştir. Bunların% 23'ü yaşlı hastalar da dahil olmak üzere 541 hasta ABD kontrollü klinik çalışmalara katıldı ve 251'i yabancı kontrollü klinik çalışmalarda incelendi. Trandolapril ve Verapamil Hidroklorür ile yapılan klinik çalışmalarda, bu kombinasyon ilacına özgü hiçbir olumsuz deneyim gözlenmemiştir. Ortaya çıkan olumsuz deneyimler, daha önce verapamil veya trandolapril ile bildirilenlerle sınırlıdır. Trandolapril ve Verapamil Hidroklorür, 1 yıl veya daha uzun süre tedavi edilen 272 hastada uzun süreli güvenlik açısından değerlendirilmiştir. Olumsuz deneyimler genellikle hafif ve geçiciydi.
ABD plasebo kontrollü hipertansiyon çalışmalarında advers olaylar nedeniyle tedavinin kesilmesi, Trandolapril ve Verapamil Hidroklorür ve plasebo ile tedavi edilen hastaların sırasıyla% 2.6 ve% 1.9'unda gerekliydi.
Bir dizi trandolapril (0.5-8 mg) ve verapamil (120240 mg) kombinasyonları ile tedavi edilen plasebo kontrollü hipertansiyon çalışmalarında 541 hastanın% 1'inde veya daha fazlasında meydana gelen advers deneyimler aşağıda gösterilmiştir.
ABD YER ALT KOKONTROLLÜ DENEMELERİNDE Trandolapril ve Verapamil Hidroklorür HASTALARININ ≥% 1'inde DÖNÜŞÜM ETKİNLİKLERİ
Trandolapril ve Verapamil Hidroklorür (N = 541) İnsidans (% Durdurma) | PLACEBO (N = 206) İnsidans (% Durdurma) | |
AV Blok Birinci Derece | 3.9 (0.2) | 0.5 (0.0) |
Bradikardi | 1.8 (0.0) | 0.0 (0.0) |
Bronşit | 1.5 (0.0) | 0.5 (0.0) |
Göğüs Ağrısı | 2.2 (0.0) | 1.0 (0.0) |
Kabızlık | 3.3 (0.0) | 1.0 (0.0) |
Öksürük | 4.6 (0.0) | 2.4 (0.0) |
İshal | 1.5 (0.2) | 1.0 (0.0) |
Baş dönmesi | 3.1 (0.0) | 1.9 (0.5) |
Dispne | 1.3 (0.4) | 0.0 (0.0) |
Ödem | 1.3 (0.4) | 2.4 (0.0) |
Yorgunluk | 2.8 (0.4) | 2.4 (0.0) |
Baş ağrısı + | 8.9 (0.0) | 9.7 (0.5) |
Artan Karaciğer Enzimleri * | 2.8 (0.2) | 1.0 (0.0) |
Bulantı | 1.5 (0.2) | 0.5 (0.0) |
Ağrı Ekstremitesi (leri) | 1.1 (0.2) | 0.5 (0.0) |
Ağrı Sırtı + | 2.2 (0.0) | 2.4 (0.0) |
Ağrı Eklem (ler) i | 1.7 (0.0) | 1.0 (0.0) |
Üst Solunum Yolu Enfeksiyonu + | 5.4 (0.0) | 7.8 (0.0) |
Üst Solunum Yolu Tıkanıklığı + | 2.4 (0.0) | 3.4 (0.0) |
* Ayrıca SGPT, SGOT, Alkalin Fosfataz artışını içerir + Plasebo grubunda advers olay insidansı Trandolapril ve Verapamil Hidroklorür hastalarından daha yüksektir |
Kontrollü veya kontrolsüz çalışmalarda (N = 990) ve daha az sıklıkta, klinik olarak anlamlı olan, birlikte diüretik ile veya eşzamanlı diüretik olmadan trandolapril / verapamil kombinasyonları ile tedavi edilen hastaların% 0.3'ünde veya daha fazlasında meydana gelen muhtemelen, muhtemelen veya kesinlikle ilaç tedavisi ile ilgili diğer klinik advers deneyimler (italiklerde) aşağıdakileri içerir:
Kardiyovasküler
Anjina, AV blok ikinci derece, demet dal bloğu, ödem, kızarma, hipotansiyon, miyokard enfarktüsü, çarpıntı, erken ventriküler kasılmalar, spesifik olmayan ST-T değişiklikleri, senkop yakınında, taşikardi.
Merkezi Sinir Sistemi
Uyuşukluk, hipestezi, uykusuzluk, denge kaybı, parestezi, baş dönmesi.
Dermatolojik
Kaşıntı, döküntü.
Duygusal, Zihinsel, Cinsel Devletler
Anksiyete, iktidarsızlık, anormal mentasyon.
Göz, Kulak, Burun, Boğaz
Epistaksis, kulak çınlaması, üst solunum yolu enfeksiyonu, bulanık görme.
Gastrointestinal
İshal, hazımsızlık, ağız kuruluğu, bulantı.
Genel Vücut Fonksiyonu
Göğüs ağrısı, halsizlik, halsizlik.
Genitourinary
Endometriozis, hematüri, noktüri, poliüri, proteinüri.
Hemopoietik
Azalmış lökositler, azalmış nötrofiller.
Kas-iskelet sistemi
Artraljiler / miyaljiler, gut (artmış ürik asit).
Pulmoner
Dispne.
Anjiyoödem
ABD'de ve yabancı çalışmalarda Trandolapril ve Verapamil Hidroklorür alan 3 (% 0.15) hastada anjiyoödem bildirilmiştir (N = 1.957). Laringeal ödem ile ilişkili anjiyoödem ölümcül olabilir. Yüz, ekstremiteler, dudaklar, dil, glotis ve / veya gırtlak anjiyoödem meydana gelirse, Trandolapril ve Verapamil Hidroklorür ile tedavi kesilmeli ve derhal uygun tedavi uygulanmalıdır (bkz UYARILAR).
Hipotansiyon
(Görmek UYARILAR). Hipertansif hastalarda hipotansiyon% 0.6'da ve senkop yakınında% 0.1'de meydana geldi. Hipotansiyon veya senkop, hipertansif hastaların% 0.4'ünde tedavinin kesilmesine neden oldu.
Akut Kardiyovasküler Advers Reaksiyonların Tedavisi
Terapi gerektiren kardiyovasküler advers reaksiyonların sıklığı nadirdir, bu nedenle tedavileri ile ilgili deneyim sınırlıdır. Trandolapril ve Verapamil Hidroklorürün (verapamil bileşeni) oral uygulamasını takiben şiddetli hipotansiyon veya tam AV bloğu meydana geldiğinde, uygun acil durum önlemleri derhal uygulanmalıdır, örn.intravenöz olarak uygulanan izoproterenol HCl, levarterenol bitartrat, atropin (hepsi normal dozlarda) veya kalsiyum glukonat (% 10 çözelti). Hipertrofik kardiyomiyopatisi (IHSS) olan hastalarda, kan basıncını korumak için alfa-adrenerjik ajanlar (fenilefrin, metaraminol bitartrat veya metoksamin) kullanılmalı ve izoproterenol ve levarterenolden kaçınılmalıdır. Daha fazla destek gerekirse, inotropik ajanlar (dopamin veya dobutamin) uygulanabilir. Gerçek tedavi ve dozaj, tedavi eden doktorun ciddiyetine ve klinik durumuna ve yargı ve deneyimine bağlı olmalıdır.
Diğer
Tek tek bileşenlerle bildirilen diğer olumsuz deneyimler (tabloda yer alan ve yukarıda listelenenlere ek olarak) aşağıda listelenmiştir.
Verapamil Bileşeni
Kardiyovasküler
(Görmek UYARILAR). CHF / pulmoner ödem, AV bloğu 3 °, atriyoventriküler ayrışma, klodikasyon, purpura (vaskülit), senkop.
Sindirim Sistemi
Dişeti hiperplazisi. Tersinir, (verapamilin kesilmesinden sonra) obstrüktif olmayan, paralitik ileus verapamil kullanımı ile ilişkili olarak seyrek olarak bildirilmiştir.
Hemik ve Lenfatik
Ekimoz veya morarma.
Sinir Sistemi
Serebrovasküler olay, konfüzyon, psikotik belirtiler, titreme, uyku hali.
Cilt
Ekzantem, saç dökülmesi, hiperkeratoz, makula, terleme, ürtiker, Stevens-Johnson sendromu, eritema multiform.
Ürogenital
Jinekomasti, galaktore / hiperprolaktinemi, artan idrara çıkma, sivilceli adet kanaması.
Trandolapril Bileşeni
Duygusal, Zihinsel, Cinsel Devletler
Azalmış libido.
Gastrointestinal
Pankreatit.
Klinik Laboratuvar Test Bulguları
Hematoloji
(Görmek UYARILAR). Düşük beyaz kan hücreleri, düşük nötrofiller, düşük lenfositler, düşük trombositler.
Serum Elektrolitleri
Hiperkalemi (bkz ÖNLEMLER), hiponatremi.
Böbrek Fonksiyon Testleri
Hidroklorotiyazid tedavisi olan veya olmayan Trandolapril ve Verapamil Hidroklorür alan hastaların sırasıyla yüzde 1.1 ve yüzde 0.3'ünde kreatinin ve kan üre azot düzeylerinde artış meydana geldi. Bu artışların hiçbiri tedavinin kesilmesini gerektirmedi. Bu laboratuvar değerlerinde artışların böbrek yetmezliği olan veya diüretik ile tedavi edilen hastalarda ortaya çıkma olasılığı daha yüksektir ve diğer ACE inhibitörleri ile deneyime dayanarak, özellikle böbrek arteri stenozu olan hastalarda muhtemel olması beklenir (bkz ÖNLEMLER ve UYARILAR).
Karaciğer Fonksiyon Testleri
Karaciğer enzimlerinde (SGOT, SGPT, LDH ve alkalin fosfataz) ve / veya serum bilirubin yükselmeleri meydana geldi. Yüksek karaciğer enzimleri için kesilme hastaların yüzde 0,9'unda meydana gelmiştir (bkz UYARILAR).
Pazarlama Sonrası Deneyim
Verapamil ve kolşisin kombine kullanımı ile ilişkili tek bir pazarlama sonrası felç raporu (tetraparesis) vardır. Bu, CYP3A4 ve verapamil tarafından P-gp inhibisyonu nedeniyle kan-beyin bariyerini geçen kolşisin neden olmuş olabilir. Verapamil ve kolşisin birlikte kullanılması önerilmez (bkz ÖNLEMLER ve İLAÇ ETKİLEŞİMLERİ).
Trandolapril ve Verapamil Hidroklorür ile aşırı doz tedavisi hakkında özel bir bilgi mevcut değildir.
Verapamil Bileşeni
Verapamil ile aşırı doz belirgin hipotansiyon, bradikardi ve iletim sistemi anormalliklerine yol açabilir (örn.AV ayrışması ile kavşak ritmi ve asistol dahil yüksek derece AV bloğu). Hipoperfüzyona sekonder diğer semptomlar (ör.metabolik asidoz, hiperglisemi, hiperkalemi, böbrek fonksiyon bozukluğu ve konvülsiyonlar) görülebilir.
Tüm verapamil doz aşımlarını ciddi olarak tedavi edin ve tercihen sürekli hastane bakımı altında en az 48 saat gözlem yapın. Sürekli salım formülasyonu ile gecikmiş farmakodinamik sonuçlar ortaya çıkabilir. Verapamil'in gastrointestinal geçiş süresini azalttığı bilinmektedir. Doz aşımı durumunda, ISOPTIN SR tabletlerinin bazen mide veya bağırsaklarda beton oluşturduğu bildirilmiştir. Bu betonlar karnın düz radyografilerinde görülmemiştir ve gastrointestinal boşalmanın hiçbir tıbbi yolunun çıkarılmasında etkinliği kanıtlanmamıştır. Semptomlar alışılmadık şekilde uzadığında aşırı doz vakalarında endoskopi makul olarak düşünülebilir. Verapamil hemodiyaliz ile giderilemez.
Doz aşımı tedavisi destekleyici olmalıdır. Beta adrenerjik stimülasyon veya kalsiyum çözeltilerinin parenteral uygulaması yavaş kanal boyunca kalsiyum iyon akısını artırabilir ve verapamil ile kasıtlı doz aşımının tedavisinde etkili bir şekilde kullanılmıştır. Aşağıdaki önlemler düşünülebilir:
Bradikardi ve İletim Sistemi Anormallikleri
Atropin, izoproterenol ve kardiyak pacing.
Hipotansiyon
İntravenöz sıvılar, vazopresörler (ör., dopamin, dobutamin), kalsiyum çözeltileri (ör.,% 10 kalsiyum klorür çözeltisi).
Kardiyak Arızalar
İnotropik ajanlar (ör., izoproterenol, dopamin, dobutamin), diüretikler. Asistol, kardiyopulmoner resüsitasyon dahil olağan önlemlerle ele alınmalıdır.
Trandolapril Bileşeni
Oral LD50 farelerde trandolapril erkeklerde 4875 mg / kg ve kadınlarda 3990 mg / kg idi. Sıçanlarda, 5000 mg / kg'lık bir oral doz düşük mortaliteye neden oldu (5 erkekten 1 erkek; 0 kadın). Köpeklerde, 1000 mg / kg'lık bir oral doz mortaliteye neden olmadı ve anormal klinik belirtiler gözlenmedi.
İnsanlarda en olası klinik bulgu, şiddetli hipotansiyona atfedilebilen semptomlar olacaktır. Trandolapril ve metabolitlerinin serum seviyelerinin laboratuvar belirlemeleri yaygın olarak mevcut değildir ve bu tür tespitler her durumda trandolapril doz aşımının yönetiminde yerleşik bir role sahip değildir. Fizyolojik manevraların (ör., idrarın pH'ını değiştirmek için manevralar) trandolapril ve metabolitlerinin ortadan kaldırılmasını hızlandırabilir. Trandolapril veya trandolaprilatın hemodiyaliz ile vücuttan yararlı bir şekilde çıkarılıp çıkarılamayacağı bilinmemektedir.
Anjiyotensin II muhtemelen trandolapril doz aşımı ortamında spesifik bir antagonist antidot görevi görebilir, ancak anjiyotensin II dağınık araştırma tesislerinin dışında esasen kullanılamaz. Trandolaprilin hipotansif etkisi vazodilatasyon ve etkili hipovolemi ile elde edildiğinden, trandolapril doz aşımının normal salin çözeltisi infüzyonu ile tedavi edilmesi mantıklıdır.