The incidence of adverse events during treatment with ADALAT CC at doses up to 90 mg per day were derived from multi-center placebo-controlled clinical trials in 370 hypertensive patients. Aténolol 50 mg once daily was used simultaneously in 187 of 370 patients ADALAT CC, and in 64 of 126 patients who received a placebo. All adverse events reported during ADALAT CC therapy were tabulated, regardless of their causal relationship with the drug. When the frequency of adverse events with ADALAT CC and placebo is similar causal relationship can be established. The following adverse events were reported with an incidence of 3% or less in daily doses up to 90 mg of: Whole Body / systemic: chest pain, leg pain Central Nervous System: paresthesia, vertigo Dermatological rash Digestive: constipation Musculo-squelettiques: leg cramps Respiratory: epistaxis, rhinitis Urogénitaux: impotence, urinary frequency Other adverse events reported with an incidence of less than 1.0% were: Whole Body / systemic allergic reaction, asthenia, cellulitis, substernal chest pain, chills, swelling of the face, abnormal laboratory analysis, malaise, pain in the neck, pelvic pain, pain, photosensitivity reaction Cardiovascular: atrial fibrillation, bradycardia, cardiac arrest, extrasystole, hypotension, headaches, palpitations, phlebitis, hypotension, tachycardia, skin angiectases Central Nervous System: anxiety, confusion, decreased libido, depression, hypertension, hypesthesia, insomnia, somnolence Dermatological: itching, sweating Gastrointestinal abdominal pain, diarrhea, dry mouth, dysphagia, dyspepsia, belching, esophagitis, flatulence, gastrointestinal disorders, gastrointestinal bleeding, increased GGT, disorder gum, gum bleeding, vomiting Hématologiques: eosinophilia, lymphadenopathy Metabolic: gout, weight loss Musculosksletal: arthralgia, arthritis, joint disorders, myalgia, myasthenia Respiratory: dyspnea, cough, rales, pharyngitis, stridor Sens: abnormal vision, amblyopia, conjunctivitis, diplopia, eye problems, eye hemorrhage, tinnitus Urogénitaux / Reproduction: dysuria, kidneys calculation, nocturia, breast engorgement, polyuria, urogenital disorders The following side effects have rarely been reported in patients who received nifedipine in base coat or other formulations: hepatitis allergenic, alopecia, anaphylactic reaction, anemia, arthritis with ANA (+), depression , erythromelalgia, exfoliative dermatitis, fever, gingival hyperplasia, gynecomastia, Hyperglycemia, jaundice, leukopenia, mood changes, muscle cramps, nervousness, paranoid syndrome, purpura, tremor, sleep disturbances, the syndrome Stevens, syncope, taste perversion, thrombocytopenia, toxic epidermal necrolysis, transient blindness, at the peak level of plasma, tremor and hives. Drug Interactions Beta Blocker: (See WARNINGS). Nifedipine is eliminated primarily by metabolism and is a CYP3A. Inhibitors and inducers of CYP3A4 can have an impact on exposure to nifedipine and therefore desirable, and its adverse effects. In vitro and in vivo, the data indicate that nifedipine can inhibit the metabolism of drugs that are substrates of CYP3A, increasing exposure to other drugs. Nifedipine is a vasodilator, and the administration of other drugs affecting blood pressure may result in pharmacodynamic interactions. CardiovascularDrugs Antiarrhythmic Quinidine: Quinidine is a CYP3A and has been shown to inhibit CYP3A in vitro. The administration of multiple doses of quinidine sulfate, 200 mg t.i.d. And nifedipine, 20 mg t.i.d. increased Cmax and AUC of nifedipine in healthy volunteers by factors of 2.30 and 1.37, respectively. The heart rate in the first interval after dosing was increased by 17.9 beats per minute. Exposure to quinidine has not changed especially in the presence of nifedipine. Monitor heart rate and the adjustment of the dose of nifedipine, if necessary, are recommended when quinidine is added to treatment with nifedipine. Flécaïnide: There has been too little experience with the co-administration of TAMBOCOR with nifedipine to recommend concurrent use. Calcium channel blockers Diltiazem: Pretreatment of healthy volunteers with 30 mg or 90 mg t.i.d. Diltiazem p.o. Increase of AUC of nifedipine after a single dose of 20 mg of nifedipine by a factor of 2.2 and 3.1, respectively. The values of nifedipine Cmax increased by a factor of 2.0 and 1.7, respectively. Caution should be exercised when administered diltiazem and nifedipine and a reduction in the dose of nifedipine should be considered. Verapamil: Verapamil, a CYP3A inhibitor, to inhibit the metabolism of nifedipine and increase the exposure to nifedipine during concurrent. Blood pressure should be measured and reduction of the dose of nifedipine considered. ACE Inhibitors Bénazépril: In healthy volunteers receiving a single dose of 20 mg nifedipine ER and benazepril 20 mg, plasma concentrations of nifedipine benazepril and in the presence and absence of others were not statistically significant. A hypotensive effect was only seen after administration of the two drugs. The tachycardic effect of nifedipine was attenuated in the presence of benazepril. Angiotensin II II blockers Irbésartan: In vitro studies showed a significant inhibition of the formation of oxidized metabolites irbesartan by nifedipine. However, in clinical studies, concomitant nifedipine had no effect on the pharmacokinetics irbesartan. Candesartan: No significant drug interactions have been reported in studies with candesartan cilexitil administered with nifedipine. Because candesartan is not significantly metabolized by cytochrome P450 and therapeutic concentrations has no effect on cytochrome P450, interactions with drugs that inhibit or are metabolized by these enzymes is not expected. Beta Blocker ADALAT CC was well tolerated when administered in combination with beta-blockers in 187 hypertensive patients in a placebo-controlled clinical trial. However, there have been occasional reports literature suggesting that the combination of nifedipine and beta-blocker drugs can increase the risk of a heart attack, severe hypotension or worsening angina in patients with cardiovascular disease. Surveillance clinic is recommended and an adjustment of the dose of nifedipine should be considered. Timolol: Hypotension is more likely to occur if dihydropryridine calcium antagonists such as nifedipine are given with timolol. Central Alpha1-blockers Doxazosin: in healthy volunteers participating in a multiple-dose nifedipine doxazosin interaction study received 2 mg doxazosin q.d. Alone or in combination with 20 mg of nifedipine ER b.i.d. The administration of nifedipine resulted in a decrease in AUC and Cmax doxazosin 83% and 86% by value in the absence of nifedipine, respectively. In the presence of doxazosin, AUC and Cmax of nifedipine were increased by a factor of 1.13 and 1.23, respectively. Compared with monotherapy nifedipine, blood pressure was lower in the presence of doxazosin. Blood pressure should be measured at the doxazosin is administered in combination with nifedipine, and a reduction in the dose of nifedipine considered. Digitalis Digoxin: As there have been isolated cases of patients with high levels of digoxin, and there is a possible interaction between digoxin and ADALAT CC, it is recommended that the digoxin levels be monitored at the beginning, adaptation and abandonment ADALAT CC to avoid possible over - or under-Scans. Antithrombotic Coumarines: There have been rare cases of increase in the prothrombin time in patients taking coumarin anticoagulants nifedipine who was administered. However, the relationship with nifedipine therapy remains uncertain. Inhibitors of platelet aggregation Clopidogrel: No clinically significant pharmacodynamic interactions have been observed when clopidrogrel was administered with nifedipine. The tirofiban: Co-administration of nifedipine did not alter exposure to tirofiban important. No cardiovascular drugs Antifungal Drugs Ketoconazole, fluconazole and itraconazole are CYP3A inhibitors and may inhibit the metabolism of nifedipine and increase the exposure to nifedipine during concurrent. Blood pressure should be monitored and a reduction in the dose of nifedipine considered. Antisécrétoire Drugs Omeprazole: In healthy volunteers receiving a single dose of 10 mg of nifedipine, AUC and Cmax nifedipine after pretreatment with omeprazole 20 mg q.d. For 8 days were 1.26 and 0.87 times those after pretreatment with placebo. Pretreatment or administration of omeprazole has no impact on the effect of nifedipine on blood pressure or heart rate. The impact of omeprazole on nifedipine is not likely to be of clinical relevance. Pantoprazole: In healthy volunteers or exposure to the drug has been changed significantly in the presence of other drugs. Ranitidine: Five studies in healthy volunteers investigated the impact of multiple doses of ranitidine on single or multiple dose pharmacokinetics of nifedipine. Two studies have investigated the impact of ranitidine coadministered on blood pressure in the nifedipine in hypertensive subjects. The administration of ranitidine had no effect on exposure to nifedipine that affected blood pressure or heart rate in the normotensive or hypertensive subjects. Cimetidine: Five studies in healthy volunteers investigated the impact of multiple doses of cimetidine single or multiple dose pharmacokinetics of nifedipine. Two studies have investigated the impact of coadministered cimetidine on blood pressure in the nifedipine in hypertensive subjects. Normotendus subjects receiving a single dose of 10 mg and multiple doses of up to 20 mg of nifedipine t.i.d. Alone or with cimetidine up to 1000 mg / day, the values of the AUC nifedipine in the presence of cimetidine were between 1.52 and 2.01 times those of the absence of cimetidine. The Cmax values of nifedipine in the presence of cimetidine were increased by factors ranging between 1.60 and 2.02. Increased exposure to nifedipine by cimetidine was accompanied by changes in blood pressure or heart rate normotensive subjects. Hypertendus patients receiving 10 mg q.d. Nifedipine alone or in combination with cimetidine 1000 mg q.d. Has also experienced changes in blood pressure during cimetidine was added to nifedipine. The interaction between cimetidine and nifedipine is the clinical efficacy and blood pressure should be monitored and a reduction in the dose of nifedipine considered. Antibacterial Drugs Quinupristin / Dalfopristin: In vitro, the drug interaction studies have shown that quinupristin / dalfopristin significantly inhibits the CYP3A metabolism of nifedipine. Concomitant administration of quinupristin / dalfopristin and nifedipine (repeated oral dose) in healthy volunteers increased the AUC and Cmax for nifedipine by factors of 1.44 and 1.18, respectively, compared to nifedipine monotherapy. At the co-administration of quinupristin / dalfopristin with nifedipine, blood pressure should be monitored and a reduction in the dose of nifedipine considered. Erythromycin: Erythromycin, a CYP3A inhibitor, to inhibit the metabolism of nifedipine and increase the exposure to nifedipine during concurrent. Blood pressure should be measured and reduction of the dose of nifedipine considered. Antitubercular Drugs Rifampin: Pretreatment healthy volunteers with 600 mg / day rifampicin p.o. Reduced exposure to oral nifedipine (20 µ g / kg) to 13%. Exposure to nifedipine rifampicin injecting the same treatment was decreased by 70%. Adjustment of the dose of nifedipine may be necessary if nifedipine is administered in combination with rifampin. Rifapentine: Rifapentine as inducers of CYP3A4, can reduce exposure to nifedipine. An adjustment of the dose of nifedipine when administered with rifapentine should be considered. Antiviral Drugs Amprenavir, atanazavir, delavirine, fosamprinavir, indinavir, ritonavir and nelfinavir, as CYP3A inhibitors can inhibit the metabolism of nifedipine and increase the exposure to nifedipine. Caution is warranted and clinical monitoring of patients recommended. CNS Drugs Néfazodone, a CYP3A inhibitor, to inhibit the metabolism of nifedipine and increase the exposure to nifedipine during concurrent. Blood pressure should be monitored and a reduction in the dose of nifedipine considered. Valproic acid may increase concomitant exposure to nifedipine in the course of treatment. Blood pressure should be monitored and a reduction in the dose of nifedipine considered. Phenytoin: Nifedipine is metabolized by CYP3A4. The administration of nifedipine 10 mg capsules and 60 mg of nifedipine compressed base coat with phenytoin, an inducer of CYP3A4, reduces the AUC and Cmax nifedipine approximately 70%. When using nifedipine with phenytoin, the clinical response to nifedipine should be monitored and adjusted as necessary dosage. Phenobarbital and carbamazepine as inducers of CYP3A may reduce exposure to nifedipine. Adjustment of the dose of nifedipine may be necessary if phenobarbital, phenytoin or carbamazepine is administered. Antiemetic Drugs Dolasetron: In patients taking dolasetron by the oral or intravenous and nifedipine, no effect was shown on the clearance of hydrodolasetron. Immunosuppressive Drugs Tacrolimus: Nifedipine has been shown to inhibit the metabolism in vitro, tacrolimus. Transplant patients on tacrolimus and nifedipine required from 26% to 38% lower dose levels than patients not receiving nifedipine. Nifedipine can increase exposure to tacrolimus. When nifedipine is administered in combination with tacrolimus blood concentrations of tacrolimus should be monitored and a reduction in the dose of tacrolimus considered. Sirolimus: A single 60 mg of nifedipine and a single 10 mg oral sirolimus solution were administered to 24 healthy volunteers. Clinically significant pharmacokinetic drug interactions have not been met. Glucose lowering drugs Pioglitazone: The administration of pioglitazone for 7 days with 30 mg of nifedipine ER administered orally q.d. Over 4 days for men and women volunteers led to least squares mean (90% CI) for the values unchanged nifedipine of 0.83 (0,73-0,95) for the Cmax and 0.88 (0.80 -0.96) De AUC nifedipine on monotherapy. Due to the high variability of nifedipine pharmacokinetics, the clinical significance of this finding is unknown. Rosiglitazone: The administration of rosiglitazone (4 mg b.i.d.) showed a clinically relevant have no effect on the pharmacokinetics of nifedipine. Metformin: a single dose of nifedipine metformin interaction study in normal healthy volunteers showed that the co-administration of nifedipine metformin increased plasma Cmax and AUC by 20% and 9%, respectively, and increased the amount metformin excreted in the urine. Tmax and half were not affected. Nifedipine seems to favor the absorption of metformin. Miglitol: No effects of miglitol was observed on the pharmacokinetics and pharmacodynamics of nifedipine. Répaglinide: The administration of 10 mg of nifedipine with a single dose of 2 mg of repaglinide (after 4 days nifedipine 10 mg t.i.d. and repaglinide 2 mg t.i.d.) gave rise to the 'AUC and Cmax unchanged values for the two drugs. Acarbose: Nifedipine tends to produce hyperglycemia and can lead to loss of control of glucose. If nifedipine is administered in combination with acarbose, blood glucose should be monitored carefully and adjustment of the dose of nifedipine considered. Drugs interfere with the absorption food Orlistat: In 17 normal-weight patients receiving orlistat 120 mg t.i.d. During 6 days, orlistat did not change the bioavailability of 60 mg of nifedipine (extended release tablets). Dietary Supplements Grapefruit Juice: In healthy volunteers, a single dose co-administration of 250 mL double strength grapefruit juice with 10 mg of nifedipine AUC and Cmax increased by a factor of 1.35 and 1.13, respectively. Ingestion of repeated doses of grapefruit juice (5 x 200 mL in 12 hours) after administration of 20 mg of nifedipine ER increase in AUC and Cmax nifedipine by a factor of 2.0. Grapefruit juice should be avoided by patients on nifedipine. The consumption of grapefruit juice should be discontinued at least 3 days before starting patients on nifedipine. Herbals St. John's Wort: inducers of CYP3A4 and may decrease exposure to nifedipine. Adjustment of the dose of nifedipine may be necessary if St. John's Wort is administered. CYP2D6 probe drug Debrisoquine: In healthy volunteers, pretreatment, nifedipine 20 mg t.i.d. During 5 days did not change the metabolic rate of hydroxydebrisoquine to debrisoquine measured in the urine after a single dose of 10 mg debrisoquine. Thus, it is unlikely that nifedipine in vivo inhibits the metabolism of other drugs that are substrates of CYP2D6. Excessifs Hypotension Although in most patients hypotensive effect of nifedipine is modest and well tolerated, patients were sometimes excessive and poorly tolerated hypotension. These responses have generally held during initial titration or at the subsequent upward adjustment of the dosage, and may be more likely in patients using concomitant beta-blockers. Hypotension severe and / or increased fluid volume requirements have been reported in patients who received immediate capsules with a beta-blocking agent and who suffered heart bypass using the higher dose of fentanyl anesthesia. Interaction with high doses of fentanyl appears to be due to the combination of nifedipine and a beta blocker, but the possibility that it can occur only with nifedipine, with low doses of fentanyl in other surgical procedures , or other narcotic analgesics can not be Écartée. In patients treated with nifedipine surgery where the use of high doses of fentanyl anesthesia is planned, the doctor must be aware of these potential problems and, if the patient's condition allows, sufficient time (at least 36 hours) should be allowed to nifedipine washing In the body prior to surgery. Angina increased and / or myocardial infarction Rarely, patients, especially those with severe obstructive coronary artery disease, have developed well-documented increase in the frequency, duration and / or severity of angina or acute myocardial infarction with nifedipine departure or when the increase of the dose. The mechanism of this effect is not established. Bêta-bloquant withdrawal If we adopt a beta-blocker, it is important to recover doses, if possible, rather than stop abruptly before starting nifedipine. Patients recently withdrawn from beta blockers can develop a withdrawal syndrome to increased angina, probably due to increased sensitivity to catecholamines. Opening of nifedipine treatment will not prevent this event and, on occasion, has been reported to increase it. Congestive Heart Failure Rarely, patients (usually while receiving a beta-blocker) developed heart failure after nifedipine. Patients with aortic stenosis can be tight at greater risk for such an event because unloading effect of nifedipine should be less benefit to these patients, because of their fixed impedance across the aortic valve flow. PRECAUTIONS General Hypotension: Because nifedipine decreases peripheral vascular resistance, careful monitoring of blood pressure during the first administration and titration of ADALAT CC is suggested. Close observation is particularly suitable for patients already taking drugs which are known to lower blood pressure (see WARNINGS). Peripheral edema: Mild to moderate peripheral edema occurs in a dose manner with ADALAT CC. Placebo subtracted rate is about 8% to 30 mg, 12% at 60 mg and 19% at 90 mg per day. The edema is a localized phenomenon, thought to be associated with the dependent vasodilation of arterioles and small blood vessels and not due to a dysfunction of the left ventricle, or generalized fluid retention. With patients whose hypertension is complicated by congestive heart failure, care must be taken to differentiate this peripheral edema of the effects of increased left ventricular dysfunction. Lab Tests Rare, mostly ephemeral, but sometimes significant elevations of enzymes such as alkaline phosphatase, CPK, LDH, SGOT and SGPT were noted. The relationship to therapy nifedipine is uncertain in most cases, but in some estimates. These laboratory abnormalities have rarely been associated with clinical symptoms, but with or without cholestatic jaundice has been reported. A slight increase (4%) averaged alkaline phosphatase was observed in patients treated with ADALAT CC This finding is an isolated case and it rarely resulted in values that were outside the normal range. Rare cases of hepatitis have been reported allergic with nifedipine treatment. In controlled studies, ADALAT CC has no adverse effect on serum uric acid, glucose, cholesterol or potassium. Nifedipine, like other calcium channel blockers, decreases in vitro platelet aggregation. Limited studies have shown a slight decline, but statistically significant difference in platelet aggregation and an increase of bleeding in some patients nifedipine. This is apparently a function of inhibition of calcium transport across the membrane of platelets. No clinical significance of these results has been demonstrated. Positive direct Coombs test with or without hemolytic anemia have been reported, but a causal link between the administration and nifedipine positivity of the test laboratory, including hemolysis, could not be determined. Although nifedipine has been used safely in patients with renal failure and was to exert a beneficial effect in some cases, rare reversible elevations in serum creatinine and BUN have been reported in patients with cases of 'chronic renal failure. The relationship to therapy nifedipine is uncertain in most cases, but in some estimates. Carcinogenesis, Mutagenesis, Impairment of Fertility Nifedipine was administered orally to rats for two years and has not been shown to be carcinogenic. When given to rats before mating, nifedipine caused the reduction in fertility at a dose of approximately 30 times the maximum recommended human dose. There is a report of the literature reversible reduction of the capacity of human sperm obtained from a limited number of infertile men to take recommended doses of nifedipine to bind and fertilize eggs in vitro. Mutagenicity in vivo studies were negative. Pregnancy Pregnancy Category C. In rodents, rabbits and monkeys, nifedipine has been shown to have a variety of embryotoxic, placentotoxic and fetotoxic effects, including stunted fetuses (rats, mice and rabbits), digital anomalies (rats and rabbits), deformities of ribs (Mouse), cleft palate (mouse), small and underdeveloped placenta chorionic villus (monkeys), embryonic and fetal death (rats, mice and rabbits), prolonged pregnancy (rat; not evaluated in other species), and a decrease in neonatal survival (rats; not evaluated in other species). In mg / kg or mg/m2 basis, some of the doses associated with these effects are higher than the maximum recommended human dose and some are weaker, but all are within an order of magnitude of it. Digital abnormalities seen in the nifedipine rabbits exposed pigs are strikingly similar to those seen in pigs exposed to phenytoin, and these in turn are similar to the phalangeal deformations that are most common in malformation human children with in utero exposure to phenytoin. There are no adequate and well-controlled studies in pregnant women. ADALAT CC should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Breastfeeding: Nifedipine is excreted in human milk. Therefore, a decision should be taken to stop nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Elderly: Although small pharmacokinetic studies have identified an increase in the half-life and an increase in Cmax and AUC (see CLINICAL PHARMACOLOGY: Pharmacokinetics and Metabolism), clinical studies of nifedipine did not include a sufficient number of subjects aged 65 and older to determine whether they meet Unlike the younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, the choice of the dose for an elderly patient should be cautious, usually starting at the lower end of the dosing range, reflecting the greater frequency decreased hepatic, renal, cardiac or function, and concomitant illness or other drugs. Experience with nifedipine overdose is limited. Symptoms associated with severe nifedipine overdose include loss of consciousness, drop in blood pressure, heart rhythm disturbances, metabolic acidosis, hypoxia, cardiogenic shock with pulmonary edema. Generally, overdose with nifedipine hypotension led to calls made to actively support cardiovascular, including control of the respiratory and cardiovascular function, elevation extremities, judicious use of calcium infusion pressor agents and fluids. Clearance of nifedipine should be prolonged in patients with hepatic impairment. Since nifedipine is highly protein bound, dialysis is not likely to be of no use, however, plasmapheresis may be beneficial. It was reported a case of overdose with massive extended release tablets of another formulation of nifedipine. The main effects of ingesting approximately 4800 mg of nifedipine to a young man attempted suicide because of the cocaine was induced depression initial dizziness, palpitations, hot flashes and nervousness. Within several hours of ingestion, nausea, vomiting, and generalized edema developed. No significant hypotension was evident at the presentation, 18 hours after ingestion. Blood chimie anomalies composait d'un doux, élévation passagère de la créatinémie, et des élévations modestes LDH et CPK, mais SGOT normale. Signes vitaux est restée stable, aucun électrocardiographiques anomalies ont été relevées et de la fonction rénale est revenue à la normale en 24 à 48 heures avec la routine des mesures d'appui seul. Pas de séquelles prolongées ont été observées. L'effet d'un seul 900 mg de l'ingestion de capsules de nifédipine dans un marasme anginal patient sur les antidépresseurs tricycliques était une perte de conscience en 30 minutes d'ingestion, et de l'hypotension profonde, qui a répondu à la perfusion de calcium, pressor agents et fluide de remplacement. Une variété d'anomalies de l'ECG ont été observées chez ce type de patients ayant des antécédents de bloc de branche, y compris des sinus bradycardie et divers degrés de bloc AV. Ces dicté le prophylactiques placement d'un stimulateur cardiaque ventriculaire temporaire, mais de résoudre autrement spontanément. Hyperglycémie importante a été observée d'abord en ce patient, mais les niveaux de glucose dans le plasma rapidement normalisée sans aucun traitement. Un jeune hypertendus patient avec insuffisance rénale avancée ingéré 280 mg de capsules de nifédipine à la fois, ce qui aboutirait à une hypotension marquée répondant à la perfusion de calcium et fluides. Non conduction AV anomalies, arythmie, ou prononcés changements dans la fréquence cardiaque ont été notées, et il n'existe aucune nouvelle détérioration de la fonction rénale.Arabic to English BETAChinese to English BETAChinese (Simplified to Traditional) BETAChinese (Traditional to Simplified) BETAEnglish to Arabic BETAEnglish to Chinese (Simplified) BETAEnglish to Chinese (Traditional) BETAEnglish to FrenchEnglish to GermanEnglish to ItalianEnglish to Japanese BETAEnglish to Korean BETAEnglish to PortugueseEnglish to Russian BETAEnglish to SpanishFrench to EnglishFrench to GermanGerman to EnglishGerman to FrenchItalian to EnglishJapanese to English BETAKorean to English BETAPortuguese to EnglishRussian to English BETASpanish to English
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The incidence of adverse events during treatment with ADALAT CC at doses up to 90 mg per day were derived from multi-center placebo-controlled clinical trials in 370 hypertensive patients. Aténolol 50 mg once daily was used simultaneously in 187 of 370 patients ADALAT CC, and in 64 of 126 patients who received a placebo. All adverse events reported during ADALAT CC therapy were tabulated, regardless of their causal relationship with the drug.
The most common adverse events reported with ADALAT CC was peripheral edema. This was related to the dose and frequency is 18% on ADALAT CC 30 mg per day, 22% of ADALAT CC 60 mg per day and 29% on ADALAT CC 90 mg per day, compared with 10% on placebo. Other adverse events reported in these placebo-controlled trials include:
ADALAT CC (%)
(N = 370)
PLACEBO (%)
(N = 126)
Adverse Event
Headache 19
13
Flushing / heat sensation 4
0
Dizziness 4
2
Fatigue / asthenia 4
4
Nausea 2
1
Constipation 1
0
When the frequency of adverse events with ADALAT CC and placebo is similar causal relationship can be established. The following adverse events were reported with an incidence of 3% or less in daily doses up to 90 mg of:
Whole Body / systemic: chest pain, leg pain
Central Nervous System: paresthesia, vertigo
Dermatological rash
Digestive: constipation
Musculo-squelettiques: leg cramps
Respiratory: epistaxis, rhinitis
Urogénitaux: impotence, urinary frequency
Other adverse events reported with an incidence of less than 1.0% were:
Whole Body / systemic allergic reaction, asthenia, cellulitis, substernal chest pain, chills, swelling of the face, abnormal laboratory analysis, malaise, pain in the neck, pelvic pain, pain, photosensitivity reaction
Cardiovascular: atrial fibrillation, bradycardia, cardiac arrest, extrasystole, hypotension, headaches, palpitations, phlebitis, hypotension, tachycardia, skin angiectases
Central Nervous System: anxiety, confusion, decreased libido, depression, hypertension, hypesthesia, insomnia, somnolence
Dermatological: itching, sweating
Gastrointestinal abdominal pain, diarrhea, dry mouth, dysphagia, dyspepsia, belching, esophagitis, flatulence, gastrointestinal disorders, gastrointestinal bleeding, increased GGT, disorder gum, gum bleeding, vomiting
Hématologiques: eosinophilia, lymphadenopathy
Metabolic: gout, weight loss
Musculosksletal: arthralgia, arthritis, joint disorders, myalgia, myasthenia
Respiratory: dyspnea, cough, rales, pharyngitis, stridor
Sens: abnormal vision, amblyopia, conjunctivitis, diplopia, eye problems, eye hemorrhage, tinnitus
Urogénitaux / Reproduction: dysuria, kidneys calculation, nocturia, breast engorgement, polyuria, urogenital disorders
The following side effects have rarely been reported in patients who received nifedipine in base coat or other formulations: hepatitis allergenic, alopecia, anaphylactic reaction, anemia, arthritis with ANA (+), depression , erythromelalgia, exfoliative dermatitis, fever, gingival hyperplasia, gynecomastia, Hyperglycemia, jaundice, leukopenia, mood changes, muscle cramps, nervousness, paranoid syndrome, purpura, tremor, sleep disturbances, the syndrome Stevens, syncope, taste perversion, thrombocytopenia, toxic epidermal necrolysis, transient blindness, at the peak level of plasma, tremor and hives.
Drug Interactions
Beta Blocker: (See WARNINGS).
Nifedipine is eliminated primarily by metabolism and is a CYP3A. Inhibitors and inducers of CYP3A4 can have an impact on exposure to nifedipine and therefore desirable, and its adverse effects. In vitro and in vivo, the data indicate that nifedipine can inhibit the metabolism of drugs that are substrates of CYP3A, increasing exposure to other drugs. Nifedipine is a vasodilator, and the administration of other drugs affecting blood pressure may result in pharmacodynamic interactions.
CardiovascularDrugs
Antiarrhythmic
Quinidine: Quinidine is a CYP3A and has been shown to inhibit CYP3A in vitro. The administration of multiple doses of quinidine sulfate, 200 mg t.i.d. And nifedipine, 20 mg t.i.d. increased Cmax and AUC of nifedipine in healthy volunteers by factors of 2.30 and 1.37, respectively. The heart rate in the first interval after dosing was increased by 17.9 beats per minute. Exposure to quinidine has not changed especially in the presence of nifedipine. Monitor heart rate and the adjustment of the dose of nifedipine, if necessary, are recommended when quinidine is added to treatment with nifedipine.
Flécaïnide: There has been too little experience with the co-administration of TAMBOCOR with nifedipine to recommend concurrent use.
Calcium channel blockers
Diltiazem: Pretreatment of healthy volunteers with 30 mg or 90 mg t.i.d. Diltiazem p.o. Increase of AUC of nifedipine after a single dose of 20 mg of nifedipine by a factor of 2.2 and 3.1, respectively. The values of nifedipine Cmax increased by a factor of 2.0 and 1.7, respectively. Caution should be exercised when administered diltiazem and nifedipine and a reduction in the dose of nifedipine should be considered.
Verapamil: Verapamil, a CYP3A inhibitor, to inhibit the metabolism of nifedipine and increase the exposure to nifedipine during concurrent. Blood pressure should be measured and reduction of the dose of nifedipine considered.
ACE Inhibitors
Bénazépril: In healthy volunteers receiving a single dose of 20 mg nifedipine ER and benazepril 20 mg, plasma concentrations of nifedipine benazepril and in the presence and absence of others were not statistically significant. A hypotensive effect was only seen after administration of the two drugs. The tachycardic effect of nifedipine was attenuated in the presence of benazepril.
Angiotensin II II blockers
Irbésartan: In vitro studies showed a significant inhibition of the formation of oxidized metabolites irbesartan by nifedipine. However, in clinical studies, concomitant nifedipine had no effect on the pharmacokinetics irbesartan.
Candesartan: No significant drug interactions have been reported in studies with candesartan cilexitil administered with nifedipine. Because candesartan is not significantly metabolized by cytochrome P450 and therapeutic concentrations has no effect on cytochrome P450, interactions with drugs that inhibit or are metabolized by these enzymes is not expected.
Beta Blocker
ADALAT CC was well tolerated when administered in combination with beta-blockers in 187 hypertensive patients in a placebo-controlled clinical trial. However, there have been occasional reports literature suggesting that the combination of nifedipine and beta-blocker drugs can increase the risk of a heart attack, severe hypotension or worsening angina in patients with cardiovascular disease. Surveillance clinic is recommended and an adjustment of the dose of nifedipine should be considered.
Timolol: Hypotension is more likely to occur if dihydropryridine calcium antagonists such as nifedipine are given with timolol.
Central Alpha1-blockers
Doxazosin: in healthy volunteers participating in a multiple-dose nifedipine doxazosin interaction study received 2 mg doxazosin q.d. Alone or in combination with 20 mg of nifedipine ER b.i.d. The administration of nifedipine resulted in a decrease in AUC and Cmax doxazosin 83% and 86% by value in the absence of nifedipine, respectively. In the presence of doxazosin, AUC and Cmax of nifedipine were increased by a factor of 1.13 and 1.23, respectively. Compared with monotherapy nifedipine, blood pressure was lower in the presence of doxazosin. Blood pressure should be measured at the doxazosin is administered in combination with nifedipine, and a reduction in the dose of nifedipine considered.
Digitalis
Digoxin: As there have been isolated cases of patients with high levels of digoxin, and there is a possible interaction between digoxin and ADALAT CC, it is recommended that the digoxin levels be monitored at the beginning, adaptation and abandonment ADALAT CC to avoid possible over - or under-Scans.
Antithrombotic
Coumarines: There have been rare cases of increase in the prothrombin time in patients taking coumarin anticoagulants nifedipine who was administered. However, the relationship with nifedipine therapy remains uncertain.
Inhibitors of platelet aggregation
Clopidogrel: No clinically significant pharmacodynamic interactions have been observed when clopidrogrel was administered with nifedipine.
The tirofiban: Co-administration of nifedipine did not alter exposure to tirofiban important.
No cardiovascular drugs
Antifungal Drugs
Ketoconazole, fluconazole and itraconazole are CYP3A inhibitors and may inhibit the metabolism of nifedipine and increase the exposure to nifedipine during concurrent. Blood pressure should be monitored and a reduction in the dose of nifedipine considered.
Antisécrétoire Drugs
Omeprazole: In healthy volunteers receiving a single dose of 10 mg of nifedipine, AUC and Cmax nifedipine after pretreatment with omeprazole 20 mg q.d. For 8 days were 1.26 and 0.87 times those after pretreatment with placebo. Pretreatment or administration of omeprazole has no impact on the effect of nifedipine on blood pressure or heart rate. The impact of omeprazole on nifedipine is not likely to be of clinical relevance.
Pantoprazole: In healthy volunteers or exposure to the drug has been changed significantly in the presence of other drugs.
Ranitidine: Five studies in healthy volunteers investigated the impact of multiple doses of ranitidine on single or multiple dose pharmacokinetics of nifedipine. Two studies have investigated the impact of ranitidine coadministered on blood pressure in the nifedipine in hypertensive subjects. The administration of ranitidine had no effect on exposure to nifedipine that affected blood pressure or heart rate in the normotensive or hypertensive subjects.
Cimetidine: Five studies in healthy volunteers investigated the impact of multiple doses of cimetidine single or multiple dose pharmacokinetics of nifedipine. Two studies have investigated the impact of coadministered cimetidine on blood pressure in the nifedipine in hypertensive subjects. Normotendus subjects receiving a single dose of 10 mg and multiple doses of up to 20 mg of nifedipine t.i.d. Alone or with cimetidine up to 1000 mg / day, the values of the AUC nifedipine in the presence of cimetidine were between 1.52 and 2.01 times those of the absence of cimetidine. The Cmax values of nifedipine in the presence of cimetidine were increased by factors ranging between 1.60 and 2.02. Increased exposure to nifedipine by cimetidine was accompanied by changes in blood pressure or heart rate normotensive subjects. Hypertendus patients receiving 10 mg q.d. Nifedipine alone or in combination with cimetidine 1000 mg q.d. Has also experienced changes in blood pressure during cimetidine was added to nifedipine. The interaction between cimetidine and nifedipine is the clinical efficacy and blood pressure should be monitored and a reduction in the dose of nifedipine considered.
Antibacterial Drugs
Quinupristin / Dalfopristin: In vitro, the drug interaction studies have shown that quinupristin / dalfopristin significantly inhibits the CYP3A metabolism of nifedipine. Concomitant administration of quinupristin / dalfopristin and nifedipine (repeated oral dose) in healthy volunteers increased the AUC and Cmax for nifedipine by factors of 1.44 and 1.18, respectively, compared to nifedipine monotherapy. At the co-administration of quinupristin / dalfopristin with nifedipine, blood pressure should be monitored and a reduction in the dose of nifedipine considered.
Erythromycin: Erythromycin, a CYP3A inhibitor, to inhibit the metabolism of nifedipine and increase the exposure to nifedipine during concurrent. Blood pressure should be measured and reduction of the dose of nifedipine considered.
Antitubercular Drugs
Rifampin: Pretreatment healthy volunteers with 600 mg / day rifampicin p.o. Reduced exposure to oral nifedipine (20 µ g / kg) to 13%. Exposure to nifedipine rifampicin injecting the same treatment was decreased by 70%. Adjustment of the dose of nifedipine may be necessary if nifedipine is administered in combination with rifampin.
Rifapentine: Rifapentine as inducers of CYP3A4, can reduce exposure to nifedipine. An adjustment of the dose of nifedipine when administered with rifapentine should be considered.
Antiviral Drugs
Amprenavir, atanazavir, delavirine, fosamprinavir, indinavir, ritonavir and nelfinavir, as CYP3A inhibitors can inhibit the metabolism of nifedipine and increase the exposure to nifedipine. Caution is warranted and clinical monitoring of patients recommended.
CNS Drugs
Néfazodone, a CYP3A inhibitor, to inhibit the metabolism of nifedipine and increase the exposure to nifedipine during concurrent. Blood pressure should be monitored and a reduction in the dose of nifedipine considered.
Valproic acid may increase concomitant exposure to nifedipine in the course of treatment. Blood pressure should be monitored and a reduction in the dose of nifedipine considered.
Phenytoin: Nifedipine is metabolized by CYP3A4. The administration of nifedipine 10 mg capsules and 60 mg of nifedipine compressed base coat with phenytoin, an inducer of CYP3A4, reduces the AUC and Cmax nifedipine approximately 70%. When using nifedipine with phenytoin, the clinical response to nifedipine should be monitored and adjusted as necessary dosage.
Phenobarbital and carbamazepine as inducers of CYP3A may reduce exposure to nifedipine. Adjustment of the dose of nifedipine may be necessary if phenobarbital, phenytoin or carbamazepine is administered.
Antiemetic Drugs
Dolasetron: In patients taking dolasetron by the oral or intravenous and nifedipine, no effect was shown on the clearance of hydrodolasetron.
Immunosuppressive Drugs
Tacrolimus: Nifedipine has been shown to inhibit the metabolism in vitro, tacrolimus. Transplant patients on tacrolimus and nifedipine required from 26% to 38% lower dose levels than patients not receiving nifedipine. Nifedipine can increase exposure to tacrolimus. When nifedipine is administered in combination with tacrolimus blood concentrations of tacrolimus should be monitored and a reduction in the dose of tacrolimus considered.
Sirolimus: A single 60 mg of nifedipine and a single 10 mg oral sirolimus solution were administered to 24 healthy volunteers. Clinically significant pharmacokinetic drug interactions have not been met.
Glucose lowering drugs
Pioglitazone: The administration of pioglitazone for 7 days with 30 mg of nifedipine ER administered orally q.d. Over 4 days for men and women volunteers led to least squares mean (90% CI) for the values unchanged nifedipine of 0.83 (0,73-0,95) for the Cmax and 0.88 (0.80 -0.96) De AUC nifedipine on monotherapy. Due to the high variability of nifedipine pharmacokinetics, the clinical significance of this finding is unknown.
Rosiglitazone: The administration of rosiglitazone (4 mg b.i.d.) showed a clinically relevant have no effect on the pharmacokinetics of nifedipine.
Metformin: a single dose of nifedipine metformin interaction study in normal healthy volunteers showed that the co-administration of nifedipine metformin increased plasma Cmax and AUC by 20% and 9%, respectively, and increased the amount metformin excreted in the urine. Tmax and half were not affected. Nifedipine seems to favor the absorption of metformin.
Miglitol: No effects of miglitol was observed on the pharmacokinetics and pharmacodynamics of nifedipine.
Répaglinide: The administration of 10 mg of nifedipine with a single dose of 2 mg of repaglinide (after 4 days nifedipine 10 mg t.i.d. and repaglinide 2 mg t.i.d.) gave rise to the 'AUC and Cmax unchanged values for the two drugs.
Acarbose: Nifedipine tends to produce hyperglycemia and can lead to loss of control of glucose. If nifedipine is administered in combination with acarbose, blood glucose should be monitored carefully and adjustment of the dose of nifedipine considered.
Drugs interfere with the absorption food
Orlistat: In 17 normal-weight patients receiving orlistat 120 mg t.i.d. During 6 days, orlistat did not change the bioavailability of 60 mg of nifedipine (extended release tablets).
Dietary Supplements
Grapefruit Juice: In healthy volunteers, a single dose co-administration of 250 mL double strength grapefruit juice with 10 mg of nifedipine AUC and Cmax increased by a factor of 1.35 and 1.13, respectively. Ingestion of repeated doses of grapefruit juice (5 x 200 mL in 12 hours) after administration of 20 mg of nifedipine ER increase in AUC and Cmax nifedipine by a factor of 2.0. Grapefruit juice should be avoided by patients on nifedipine. The consumption of grapefruit juice should be discontinued at least 3 days before starting patients on nifedipine.
Herbals
St. John's Wort: inducers of CYP3A4 and may decrease exposure to nifedipine. Adjustment of the dose of nifedipine may be necessary if St. John's Wort is administered.
CYP2D6 probe drug
Debrisoquine: In healthy volunteers, pretreatment, nifedipine 20 mg t.i.d. During 5 days did not change the metabolic rate of hydroxydebrisoquine to debrisoquine measured in the urine after a single dose of 10 mg debrisoquine. Thus, it is unlikely that nifedipine in vivo inhibits the metabolism of other drugs that are substrates of CYP2D6.
Excessifs Hypotension
Although in most patients hypotensive effect of nifedipine is modest and well tolerated, patients were sometimes excessive and poorly tolerated hypotension. These responses have generally held during initial titration or at the subsequent upward adjustment of the dosage, and may be more likely in patients using concomitant beta-blockers.
Hypotension severe and / or increased fluid volume requirements have been reported in patients who received immediate capsules with a beta-blocking agent and who suffered heart bypass using the higher dose of fentanyl anesthesia. Interaction with high doses of fentanyl appears to be due to the combination of nifedipine and a beta blocker, but the possibility that it can occur only with nifedipine, with low doses of fentanyl in other surgical procedures , or other narcotic analgesics can not be Écartée. In patients treated with nifedipine surgery where the use of high doses of fentanyl anesthesia is planned, the doctor must be aware of these potential problems and, if the patient's condition allows, sufficient time (at least 36 hours) should be allowed to nifedipine washing In the body prior to surgery.
Angina increased and / or myocardial infarction
Rarely, patients, especially those with severe obstructive coronary artery disease, have developed well-documented increase in the frequency, duration and / or severity of angina or acute myocardial infarction with nifedipine departure or when the increase of the dose. The mechanism of this effect is not established.
Bêta-bloquant withdrawal
If we adopt a beta-blocker, it is important to recover doses, if possible, rather than stop abruptly before starting nifedipine. Patients recently withdrawn from beta blockers can develop a withdrawal syndrome to increased angina, probably due to increased sensitivity to catecholamines. Opening of nifedipine treatment will not prevent this event and, on occasion, has been reported to increase it.
Congestive Heart Failure
Rarely, patients (usually while receiving a beta-blocker) developed heart failure after nifedipine. Patients with aortic stenosis can be tight at greater risk for such an event because unloading effect of nifedipine should be less benefit to these patients, because of their fixed impedance across the aortic valve flow.
PRECAUTIONS
General
Hypotension: Because nifedipine decreases peripheral vascular resistance, careful monitoring of blood pressure during the first administration and titration of ADALAT CC is suggested. Close observation is particularly suitable for patients already taking drugs which are known to lower blood pressure (see WARNINGS).
Peripheral edema: Mild to moderate peripheral edema occurs in a dose manner with ADALAT CC. Placebo subtracted rate is about 8% to 30 mg, 12% at 60 mg and 19% at 90 mg per day. The edema is a localized phenomenon, thought to be associated with the dependent vasodilation of arterioles and small blood vessels and not due to a dysfunction of the left ventricle, or generalized fluid retention. With patients whose hypertension is complicated by congestive heart failure, care must be taken to differentiate this peripheral edema of the effects of increased left ventricular dysfunction.
Lab Tests
Rare, mostly ephemeral, but sometimes significant elevations of enzymes such as alkaline phosphatase, CPK, LDH, SGOT and SGPT were noted. The relationship to therapy nifedipine is uncertain in most cases, but in some estimates. These laboratory abnormalities have rarely been associated with clinical symptoms, but with or without cholestatic jaundice has been reported. A slight increase (4%) averaged alkaline phosphatase was observed in patients treated with ADALAT CC This finding is an isolated case and it rarely resulted in values that were outside the normal range. Rare cases of hepatitis have been reported allergic with nifedipine treatment. In controlled studies, ADALAT CC has no adverse effect on serum uric acid, glucose, cholesterol or potassium.
Nifedipine, like other calcium channel blockers, decreases in vitro platelet aggregation. Limited studies have shown a slight decline, but statistically significant difference in platelet aggregation and an increase of bleeding in some patients nifedipine. This is apparently a function of inhibition of calcium transport across the membrane of platelets. No clinical significance of these results has been demonstrated.
Positive direct Coombs test with or without hemolytic anemia have been reported, but a causal link between the administration and nifedipine positivity of the test laboratory, including hemolysis, could not be determined.
Although nifedipine has been used safely in patients with renal failure and was to exert a beneficial effect in some cases, rare reversible elevations in serum creatinine and BUN have been reported in patients with cases of 'chronic renal failure. The relationship to therapy nifedipine is uncertain in most cases, but in some estimates.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Nifedipine was administered orally to rats for two years and has not been shown to be carcinogenic. When given to rats before mating, nifedipine caused the reduction in fertility at a dose of approximately 30 times the maximum recommended human dose. There is a report of the literature reversible reduction of the capacity of human sperm obtained from a limited number of infertile men to take recommended doses of nifedipine to bind and fertilize eggs in vitro. Mutagenicity in vivo studies were negative.
Pregnancy Pregnancy Category C. In rodents, rabbits and monkeys, nifedipine has been shown to have a variety of embryotoxic, placentotoxic and fetotoxic effects, including stunted fetuses (rats, mice and rabbits), digital anomalies (rats and rabbits), deformities of ribs (Mouse), cleft palate (mouse), small and underdeveloped placenta chorionic villus (monkeys), embryonic and fetal death (rats, mice and rabbits), prolonged pregnancy (rat; not evaluated in other species), and a decrease in neonatal survival (rats; not evaluated in other species). In mg / kg or mg/m2 basis, some of the doses associated with these effects are higher than the maximum recommended human dose and some are weaker, but all are within an order of magnitude of it.
Digital abnormalities seen in the nifedipine rabbits exposed pigs are strikingly similar to those seen in pigs exposed to phenytoin, and these in turn are similar to the phalangeal deformations that are most common in malformation human children with in utero exposure to phenytoin.
There are no adequate and well-controlled studies in pregnant women. ADALAT CC should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Breastfeeding: Nifedipine is excreted in human milk. Therefore, a decision should be taken to stop nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Elderly: Although small pharmacokinetic studies have identified an increase in the half-life and an increase in Cmax and AUC (see CLINICAL PHARMACOLOGY: Pharmacokinetics and Metabolism), clinical studies of nifedipine did not include a sufficient number of subjects aged 65 and older to determine whether they meet Unlike the younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, the choice of the dose for an elderly patient should be cautious, usually starting at the lower end of the dosing range, reflecting the greater frequency decreased hepatic, renal, cardiac or function, and concomitant illness or other drugs.
Experience with nifedipine overdose is limited. Symptoms associated with severe nifedipine overdose include loss of consciousness, drop in blood pressure, heart rhythm disturbances, metabolic acidosis, hypoxia, cardiogenic shock with pulmonary edema. Generally, overdose with nifedipine hypotension led to calls made to actively support cardiovascular, including control of the respiratory and cardiovascular function, elevation extremities, judicious use of calcium infusion pressor agents and fluids. Clearance of nifedipine should be prolonged in patients with hepatic impairment. Since nifedipine is highly protein bound, dialysis is not likely to be of no use, however, plasmapheresis may be beneficial.
It was reported a case of overdose with massive extended release tablets of another formulation of nifedipine. The main effects of ingesting approximately 4800 mg of nifedipine to a young man attempted suicide because of the cocaine was induced depression initial dizziness, palpitations, hot flashes and nervousness. Within several hours of ingestion, nausea, vomiting, and generalized edema developed. No significant hypotension was evident at the presentation, 18 hours after ingestion. Blood chimie anomalies composait d'un doux, élévation passagère de la créatinémie, et des élévations modestes LDH et CPK, mais SGOT normale. Signes vitaux est restée stable, aucun électrocardiographiques anomalies ont été relevées et de la fonction rénale est revenue à la normale en 24 à 48 heures avec la routine des mesures d'appui seul. Pas de séquelles prolongées ont été observées.
L'effet d'un seul 900 mg de l'ingestion de capsules de nifédipine dans un marasme anginal patient sur les antidépresseurs tricycliques était une perte de conscience en 30 minutes d'ingestion, et de l'hypotension profonde, qui a répondu à la perfusion de calcium, pressor agents et fluide de remplacement. Une variété d'anomalies de l'ECG ont été observées chez ce type de patients ayant des antécédents de bloc de branche, y compris des sinus bradycardie et divers degrés de bloc AV. Ces dicté le prophylactiques placement d'un stimulateur cardiaque ventriculaire temporaire, mais de résoudre autrement spontanément. Hyperglycémie importante a été observée d'abord en ce patient, mais les niveaux de glucose dans le plasma rapidement normalisée sans aucun traitement.
