Active ingredients: Nifedipine
ADALAT 10 mg soft capsules
Adalat package inserts are available for pack sizes:- ADALAT 10 mg soft capsules
- ADALAT 20 mg modified release tablets
Why is Adalat used? What is it for?
Adalat contains nifedipine as the active ingredient, which belongs to the category of calcium channel blockers - dihydropyridine derivatives.
Adalat is used to treat the following conditions:
- angina pectoris (severe chest pain in the region behind the breastbone due to insufficient blood and oxygen supply to the heart);
- chronic-stable angina pectoris, or exertional angina (a form of angina pectoris that usually occurs following exertion);
- vasospastic angina pectoris, or Prinzmetal's angina (form of angina pectoris also called variant angina that appeared without any prior correlation to stress or exertion);
- essential arterial hypertension (high blood pressure);
- hypertensive crisis (sudden increase in blood pressure);
- Raynaud's syndrome (primary and secondary), a serious disease characterized by attacks of narrowing of blood vessels, leading to reduced blood flow to the extremities of the body).
Contraindications When Adalat should not be used
Do not take Adalat
- if you are allergic to nifedipine or any of the other ingredients of this medicine (listed in section 6);
- if you are or suspect that you are pregnant (up to the 20th week) and are breastfeeding (see "Pregnancy and breastfeeding");
- in case of cardiovascular shock (sudden drop in blood pressure);
- if you are taking a medicine containing rifampicin, an antibiotic used to treat certain types of infections. In this case the levels of nifedipine in the blood may be insufficient (see "Other medicines and Adalat");
- if you suffer from unstable angina (a form of angina pectoris which occurs with the rapid and prolonged intensification of the complaints), since in this case the nifedipine in the immediate release formulation is contraindicated;
- if it has been less than 4 weeks since you suffered an acute myocardial infarction, as nifedipine in the immediate release formulation is contraindicated in this case.
Precautions for use What you need to know before taking Adalat
Talk to your doctor or pharmacist before taking Adalat.
Take special care with Adalat:
- If you have very low blood pressure (maximum pressure below 90 mm of mercury), if you have heart failure (weak heart) or aortic stenosis (severe narrowing of a valve in the heart). The active ingredient, in the immediate-release formulation, can induce an excessive drop in blood pressure with reflex tachycardia (increased heart rate not related to heart disease) which could give rise to cardiovascular complications. Very rarely angina can occur. pectoris, particularly at the start of treatment. In patients with angina pectoris, an increase in the frequency, duration and severity of attacks may occur, especially at the start of treatment. In isolated cases, the occurrence of myocardial infarction has been reported, although it has not been possible to distinguish these episodes from the natural course of the underlying disease.
- If you are pregnant, as the available information does not allow the possibility of undesirable effects on the unborn child and newborn to be excluded. For this reason, Adalat should not be used in the first 20 weeks of pregnancy (see "Do not take Adalat" and "Pregnancy and breastfeeding") and, in the following weeks, its use is reserved for women with severe hypertension, but only after a very careful evaluation of the possible risks and expected benefits and when other therapies are not suitable or have not worked. Close monitoring of blood pressure is also necessary when administering nifedipine in combination with intravenous magnesium sulfate, due to the possibility of an excessive drop in blood pressure, which could harm both the mother and the fetus.
- If you are breast-feeding, as nifedipine passes into breast milk and the effects of the baby's absorption of small amounts of nifedipine through the milk are not known (see "Pregnancy and breast-feeding").
- If your liver isn't working well. In this case, careful monitoring may be necessary and, if your condition is severe, also a reduction in the dosage of Adalat.
In patients with essential arterial hypertension or chronic stable angina pectoris treated with immediate-release formulations of nifedipine, a dose-related risk of cardiovascular complications (e.g. myocardial infarction) and mortality is possible. For this reason, nifedipine should only be used in these patients if no other treatment is appropriate.
If you have to carry out a laboratory test to determine the values of vanyl-mandelic acid in the urine (a test to diagnose a tumor of the adrenal gland), know that, in the presence of nifedipine and depending on the method used, the values may be falsely increased.
Children and adolescents
The use of Adalat 10 mg is not recommended in children and adolescents below 18 years of age as only limited efficacy and safety data are available in this population.
Interactions Which drugs or foods can change the effect of Adalat
Other medicines and Adalat
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
Nifedipine is transformed in the body through a particular system of molecules (called enzymes). If medicines that influence or use this same system are administered in combination, a reduction or increase in the concentration in the blood, and therefore in the effect, can be observed. nifedipine or the other medicine. Adjustment of the dosage of nifedipine or the other medicine and / or more frequent monitoring of your blood pressure may then be necessary.
Medicines that may modify the effect of nifedipine are:
- rifampicin (an antibiotic): never take Adalat together with medicines containing rifampicin (see "Do not take Adalat");
- diltiazem (another type of calcium channel blocker);
- certain antibiotics belonging to the macrolide class, such as erythromycin;
- certimedicinalicontrol "AIDS, such as amprenavir, indinavir, nelfinavir, ritonavir, saquinavir;
- certain medicines for fungal infections, such as ketoconazole, itraconazole, fluconazole;
- fluoxetine, nefazodone (medicines for depression);
- quinupristin / dalfopristin (antibiotic used for particular infections);
- phenytoin, carbamazepine, phenobarbitone, valproic acid (medicines against seizures);
- cimetidine, cisapride (medicines used in stomach ulcer).
Nifedipine may modify the effect of the following medicines:
- antihypertensives (used to lower blood pressure); nifedipine may accentuate the blood pressure lowering effect of other blood pressure lowering medicines. In particular, if you take medicines belonging to the group of beta-blockers in combination, your doctor will need to monitor you closely, as it may also worsen the ability of the heart to pump blood.
- digoxin, quinidine (heart medicines);
- tacrolimus (medicine used against transplant rejection).
Medicines containing the following substances do not appear to change the concentration of nifedipine in the blood and / or their metabolism is not affected by nifedipine: ajmaline (medicine for arthymias), acetylsalicylic acid at a dose of 100 mg (medicine for flu or flu symptoms) blood thinners), benazepril, doxazosin, candesartan cilexetil, irbesartan, debrisoquine, talinolol (medicines for high blood pressure), omeprazole, pantoprazole, ranitidine (medicines for heartburn), orlistat (medicine for weight loss), rosiglitazone (medicine for against diabetes), triamterene hydrochlorothiazide (diuretic).
Adalat with food and drink
Do not drink grapefruit juice while taking Adalat, as it can increase the concentration of nifedipine in your blood and prolong its effect. If you drink grapefruit juice regularly, this effect can last up to more than 3 days after stopping.
Warnings It is important to know that:
Pregnancy, breastfeeding and fertility
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.
Pregnancy
Do not take Adalat if you are in the first 20 weeks of pregnancy (see "Do not take Adalat").
Tell your doctor if you are planning a pregnancy.
Nifedipine should not be used during pregnancy unless the clinical condition of the patient requires treatment with nifedipine. The use of nifedipine should be reserved for women with severe hypertension who have not responded to treatment with standard therapy (see "Warnings and precautions").
Feeding time
The use of nifedipine during breastfeeding is not recommended because it has been reported to pass into breast milk and the effects of oral absorption of small amounts of nifedipine are unknown.
Should nifedipine treatment become necessary during this period, breastfeeding should be discontinued. For immediate release formulations, it is recommended to delay breastfeeding or milk expression for 3 or 4 hours after taking the drug. to decrease the exposure of the active agent to nifedipine (see "Warnings and precautions").
Fertility
In cases of repeated IVF failure, not attributable to other reasons, the use of nifedipine should be considered as a possible cause.
Driving and using machines
Reactions to the medicine, which vary in intensity from patient to patient, may impair the ability to drive or use machines (see "Possible side effects"). This is particularly true at the start of treatment, when changing the medicine and in relation to the intake of alcoholic beverages.
Adalat contains sunset yellow (E110)
The sunset yellow (E110) contained in the medicine can cause allergic reactions.
Dose, Method and Time of Administration How to use Adalat: Posology
Always take this medicine exactly as your doctor or pharmacist has told you. If in doubt, consult your doctor or pharmacist.
Treatment should possibly be adapted to your needs according to the severity of your disease and the response of your body. Furthermore, depending on your clinical picture, the maintenance dose should be reached gradually.
Your doctor may progressively increase the dosage to the optimal dose if you have high blood pressure with severe cerebrovascular disease, if "excessive action of nifedipine is suspected due to low body weight, if you are taking other medicines at the same time. lower your blood pressure or if you experience side effects following treatment with nifedipine.
Any adjustments to higher or lower dosages should only be made under medical supervision.
Unless otherwise prescribed, for all indications (except for hypertensive crises), the recommended dose is 1 capsule three times a day
If the therapeutic result is inadequate after approximately 2-3 days of treatment with Adalat, the dosage should be increased according to your needs.
If necessary, the dosage can be increased to a maximum of 60 mg per day (2 capsules three times per day).
In case of hypertensive crisis, the recommended dose is 1 capsule in a single dose.
If the effect on blood pressure is insufficient, an additional capsule (10 mg) can be administered at least after 30 minutes.
If the intervals between doses are shorter than 30 minutes and / or the higher dose, you could develop dangerous conditions of hypotension (low blood pressure).
Swallow the capsule whole, with some liquid, regardless of meal times.
In case of single doses of 20 mg, the time interval between two capsule intake should not be less than 2 hours.
Your doctor will decide how long Adalat treatment should be continued.
Use in elderly patients
If you are an elderly patient, a lower dosage may be required than in younger patients.
Use in patients with impaired hepatic function
If your liver is not functioning well it may be necessary to monitor your blood pressure carefully and, in severe cases, a reduction in dosage.
Overdose What to do if you have taken too much Adalat
If you take more Adalat than you should
In cases of severe nifedipine intoxication, the following symptoms have been observed: disturbances of consciousness up to coma, drop in blood pressure, fast or slow heart rate, increased blood sugar, increased acid in the blood, lack of oxygen in the blood. body, drop in blood pressure with increased fluid in the lungs.
In case of accidental ingestion / intake of an overdose of Adalat, notify your doctor immediately or go to the nearest hospital.
If you forget to take Adalat
If you have missed a dose, continue with the usual dose. Do not take a double dose to make up for a forgotten tablet.
If you stop taking Adalat
Stop taking this medicine gradually, particularly if you are taking high doses. If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Side Effects What are the side effects of Adalat
Like all medicines, this medicine can cause side effects, although not everybody gets them.
The following side effects were observed in the trials with nifedipine: common side effects (may affect up to 1 in 10 people)
- headache (headache),
- edema, including peripheral edema (generalized or swelling in the extremities),
- vasodilation (dilation of blood vessels),
- constipation (constipation),
- feeling unwell.
uncommon side effects (may affect up to 1 in 100 people)
- allergic reaction,
- allergic edema / angioedema (swelling of the skin, face and mucous membranes, including laryngeal edema, potentially life-threatening),
- anxious reactions,
- sleep disorders,
- vertigo,
- migraine (one-sided headache),
- dizziness,
- tremor,
- visual disturbances,
- tachycardia (rapid heartbeat),
- palpitations (sensation of a rapid or irregular heartbeat),
- hypotension (low blood pressure),
- syncope (fainting),
- epistaxis (nosebleed),
- nasal congestion (stuffy nose),
- gastrointestinal and abdominal pain (abdominal pain),
- nausea,
- dyspepsia (indigestion),
- flatulence (presence of gas in the intestine),
- dry mouth,
- transient increase in liver enzymes,
- erythema (redness of the skin),
- muscle cramps,
- joint swelling
- polyuria (increased amount of urine passed),
- dysuria (difficulty urinating),
- erectile dysfunction (difficulty getting and maintaining an erection),
- nonspecific pain,
- chills.
rare side effects (may affect up to 1 in 1,000 people)
- itch,
- hives (itching and small spots on the skin),
- rash,
- paraesthesia / dysesthesia (altered sensation, e.g. tingling),
- gingival hyperplasia (enlarged gums).
undesirable effects with frequency not known (frequency cannot be estimated from the available data)
- agranulocytosis (lack of some blood cells, called granulocytes),
- leukopenia (decrease in the number of white blood cells),
- anaphylactic / anaphylactoid reaction (severe allergic or allergic-like reaction),
- hyperglycemia (increased blood sugar level),
- hypoesthesia (decreased sensitivity),
- drowsiness,
- eye pain (eye pain),
- chest pain (angina pectoris),
- dyspnoea (difficulty in breathing, wheezing),
- He retched,
- insufficiency of the gastroesophageal sphincter (regurgitation),
- jaundice (yellowing of the skin and whites of the eyes),
- toxic epidermal necrolysis (severe skin disease),
- photoallergic reaction (skin reaction following exposure to the sun),
- palpable purpura (a special type of rash),
- arthralgia (pain in the joints),
- myalgia (pain in the muscles).
In dialysis patients with malignant hypertension (severe form of arterial hypertension) and hypovolemia (reduced blood volume), a marked reduction in blood pressure may occur as a result of dilation of the blood vessels.
Compliance with the instructions contained in the package leaflet reduces the risk of undesirable effects.
Reporting of side effects
If you get any side effects, including any possible side effects not listed in this leaflet, contact your doctor or pharmacist. Undesirable effects can also be reported directly via the national reporting system at http://www.agenziafarmaco.gov.it/it/responsabili. By reporting side effects you can help provide more information on the safety of this medicine. .
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton after "expires on". The expiry date refers to the last day of that month. The expiry date indicated refers to the product in intact packaging, correctly stored.
Store the tablets at a temperature not exceeding 30 ° C.
The active substance nifedipine is highly sensitive to light. Therefore the capsules must not be broken because the protection from light is no longer ensured.
Nifedipine is substantially protected from light both inside and outside the package. However, the capsules should only be removed from the package immediately before use.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Composition and pharmaceutical form
One soft capsule contains:
- The active ingredient is nifedipine. One soft capsule contains 10 mg of nifedipine.
- The other ingredients are: glycerol, purified water, sodium saccharin, mint essence, macrogol 400.
The components of the capsule are: gelatin, glycerol 85%, titanium dioxide E171, sunset yellow E110.
What Adalat looks like and contents of the pack
The package contains 50 soft capsules.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
ADALT 10 MG SOFT CAPSULES
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each soft capsule contains the active ingredient 10 mg of nifedipine
For the full list of excipients, see section 6.1
03.0 PHARMACEUTICAL FORM
Soft capsule
Oblong capsule of orange soft gelatin.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Treatment of "angina pectoris
- chronic-stable angina pectoris (exertional angina)
- vasospastic angina pectoris (Prinzmetal's angina, variant angina)
Treatment of "essential arterial hypertension
Treatment of hypertensive crisis
Treatment of the Raynaud's syndrome (primary and secondary).
In patients with essential arterial hypertension or chronic stable angina pectoris treated with immediate-release formulations of nifedipine, a dose-related increased risk of cardiovascular complications (e.g. myocardial infarction) and mortality is possible. For this reason, nifedipine should only be used in these patients if no other treatment is appropriate.
04.2 Posology and method of administration
Method of administration
Oral use
Dosage
Treatment should possibly be tailored to individual needs according to the severity of the disease and the patient's response. In any case, the maintenance dose should be reached gradually, in relation to the clinical picture.
It is recommended to progressively increase the dosage until reaching the optimal one in patients with arterial hypertension with severe cerebrovascular disease, in those in whom it is possible to suspect an "excessive action of nifedipine due to a low body weight or polytherapy with other antihypertensive drugs and in patients who experience undesirable effects following treatment with nifedipine.
Any adjustments to higher or lower dosages should only be made under medical supervision.
Unless otherwise prescribed by a doctor, the following dosage guidelines apply to adults:
1.
If the therapeutic result is inadequate after approximately 2-3 days of treatment with Adalat, the dosage should be increased according to individual needs.
If necessary, the dosage can be increased up to a maximum of 60 mg per day (2 capsules 3 times per day).
2.
If the therapeutic result is inadequate after approximately 2-3 days of treatment with Adalat, the dosage should be increased according to individual needs.
If necessary, the dosage can be increased up to a maximum of 60 mg per day (2 capsules 3 times per day).
3.
If the effect on blood pressure is insufficient, an additional capsule (10 mg) can be administered after at least 30 minutes.
If the intervals between doses were to be shorter and / or the dose higher, dangerous conditions of hypotension could occur.
4.
If the therapeutic result is inadequate after approximately 2-3 days of treatment with Adalat, the dosage should be increased according to individual needs.
If necessary, the dosage can be increased up to a maximum of 60 mg per day (2 capsules 3 times per day).
In case of concomitant administration of CYP 3A4 inhibitors or inducers, the dosage of nifedipine may need to be adjusted or even avoided (see section 4.5).
Duration of treatment
The duration of treatment must be determined by the doctor. Due to the pronounced anti-ischemic and antihypertensive activity, Adalat capsules should be discontinued gradually, particularly when high dosages are used.
Administration
Adalat capsules should be swallowed whole, with a little liquid, regardless of meals.
Grapefruit juice should be avoided (see section 4.5).
In the case of single doses of 20 mg, the time interval between two capsule intake should not be less than 2 hours.
Additional information for particular categories of patients
Children and adolescents
The safety and efficacy of Adalat 10 mg under 18 years of age has not been established. The data available to date for the use of nifedipine in hypertension are described in section 5.1.
Elderly patients
As the pharmacokinetics of nifedipine are modified in elderly subjects, these subjects may require lower doses of nifedipine than in younger patients.
Patients with impaired hepatic function
Since nifedipine is almost completely metabolised in the intestinal wall and liver, careful monitoring of blood pressure and, in severe cases, dose reduction may be necessary in patients with impaired liver function.
Patients with impaired renal function
Since nifedipine is eliminated in unchanged form by the kidney in a small percentage of the administered dose (0.1%), no dose adjustment is necessary in patients with impaired renal function.
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients (see sections 4.4 and 6.1)
Known (up to 20 weeks) or suspected pregnancy and during lactation (see section 4.6).
Cardiovascular shock.
Concomitant therapy with rifampicin, as enzyme induction does not achieve effective plasma levels of nifedipine (see section 4.5).
Nifedipine in the immediate release formulation is contraindicated in unstable angina and after acute myocardial infarction, in the first 4 weeks after the morbid event.
04.4 Special warnings and appropriate precautions for use
Caution is recommended in case of marked hypotension (systolic pressure below 90 mmHg), in cases of manifest heart failure and in cases of marked aortic stenosis.
The active ingredient, in the immediate release formulation, can induce an "excessive drop in blood pressure with reflex tachycardia that could give rise to cardiovascular complications. As with other vasoactive substances, angina pectoris can also occur very rarely (data from spontaneous reports). particular at the beginning of the treatment. Data from clinical trials confirm that the occurrence of angina pectoris attacks is uncommon. In patients with angina pectoris, an increase in the frequency, duration and severity of attacks may occur, especially at the start of treatment.
Onset of myocardial infarction has been reported in isolated cases, although it has not been possible to distinguish these episodes from the natural course of the underlying disease.
There are no safety and efficacy data from well-controlled studies in pregnant women (see section 4.5). Animal studies have shown a variety of toxic effects on the embryo, placenta and fetus (see section 4.6.) When nifedipine was administered during and after the period of organogenesis. Clinical evidence currently available. did not allow to identify a specific prenatal risk. This is despite the fact that an increase in cases of perinatal asphyxia, cesarean delivery, prematurity and intrauterine growth retardation have been reported. It is not clear whether these findings are due to hypertension itself, its treatment or a specific drug effect.
The available information does not allow to exclude the possibility of undesirable effects on the unborn and neonate. Therefore, use in pregnancy after the 20th week requires a very careful risk / benefit assessment and should only be considered if all other therapeutic options are not indicated or have proved ineffective.
Careful blood pressure control is also necessary when administering nifedipine in combination with intravenous magnesium sulphate, due to the possibility of an excessive drop in blood pressure, which could harm both the mother and the fetus.
In patients with impaired hepatic function, careful monitoring of the blood pressure situation and, in severe cases, a reduction in dosage may be necessary.
Nifedipine is metabolised via the cytochrome P450 3A4 system. All drugs that inhibit or induce this enzyme system may therefore modify the first pass effect or the clearance of nifedipine (see section 4.5).Drugs that inhibit the cytochrome P450 3A4 system, which can therefore lead to an increase in the concentrations of nifedipine, are for example:
- macrolide antibiotics (e.g. erythromycin),
- HIV protease inhibitors (e.g. ritonavir),
- azole antifungals (e.g. ketoconazole),
- the antidepressants nefazodone and fluoxetine,
- quinupristin / dalfopristin,
- valproic acid,
- cimetidine.
Upon co-administration of these drugs, blood pressure should be monitored and, if necessary, a reduction of the nifedipine dose should be considered.
The sunset yellow (E 110) contained in the medicine can cause allergic reactions.
For use in special categories of patients, see section 4.2.
04.5 Interactions with other medicinal products and other forms of interaction
Effects of other drugs on nifedipine
Nifedipine is metabolised via the cytochrome P450 3A4 system, located both in the intestinal mucosa and in the liver. All drugs that inhibit or induce this enzyme system may therefore modify the first pass effect (after oral administration) or the clearance of nifedipine (see section 4.4).
The extent and duration of interactions should be taken into account when nifedipine is administered in combination with the following drugs:
Rifampicin
Rifampicin, due to its strong enzyme induction effect on the cytochrome P450 3A4 system, significantly reduces the bioavailability of nifedipine, reducing its effectiveness. For this reason, the use of nifedipine in combination with rifampicin is contraindicated (see section 4.3).
Diltiazem
Diltiazem decreases the clearance of nifedipine so the two active substances should be combined with caution, possibly considering a reduction in the nifedipine dosage.
Upon co-administration of the following weak or moderate inhibitors of the cytochrome P450 3A4 system, blood pressure should be monitored and, if necessary, a reduction of the nifedipine dose should be considered (see section 4.2).
Macrolide antibiotics (e.g. erythromycin)
No specific study has been conducted on the interaction between nifedipine and macrolide antibiotics.
Some macrolide antibiotics are known to inhibit the cytochrome P450 3A4 mediated metabolism of other drugs and therefore a potential increase in plasma concentrations of nifedipine following co-administration of the two drugs cannot be excluded (see section 4.4).
Azithromycin, although structurally related to the macrolide class of antibiotics, is devoid of CYP 3A4 inhibiting activity.
HIV protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir)
A clinical study has not yet been conducted to investigate the potential interaction between nifedipine and certain anti-HIV protease inhibitors. Drugs of this class are known to inhibit the cytochrome P450 3A4 system. In addition, amprenavir, indinavir, nelfinavir, ritonavir, saquinavir have been shown to inhibit the cytochrome P450 3A4 mediated metabolism of nifedipine in vitro. When co-administered with nifedipine a substantial increase in plasma concentrations of nifedipine due to reduced first pass metabolism and reduced elimination cannot be excluded (see section 4.4). Following concomitant administration, blood pressure should be monitored, considering, if necessary, a reduction in the dosage of nifedipine.
Azole antifungals (ketoconazole, itraconazole, fluconazole)
A specific study on the possible interaction between nifedipine and certain azole antifungals has not yet been performed. Drugs of this class are known to inhibit the cytochrome P450 3A4 system.
When these drugs are administered orally with nifedipine, a substantial increase in the bioavailability of nifedipine linked to a reduced first pass metabolism cannot be excluded (see section 4.4).
Therefore, when administered in combination, blood pressure should be controlled considering, if necessary, the reduction of the dose of nifedipine.
Fluoxetine
A clinical study has not yet been conducted to investigate the potential interaction between nifedipine and fluoxetine. Fluoxetine has been shown to inhibit the cytochrome P450 3A4 mediated metabolism of nifedipine in vitro. Therefore, an increase in plasma concentrations of nifedipine following co-administration of the two drugs cannot be excluded (see section 4.4).
When fluoxetine is co-administered with nifedipine, blood pressure should be controlled considering, if necessary, a reduction in the dose of nifedipine.
Nefazodone
A clinical study on the possible interaction between nifedipine and nefazodone has not yet been performed. Nefazodone is known to inhibit cytochrome P450 3A4 mediated metabolism of other drugs. Therefore, an increase in plasma concentrations of nifedipine following concomitant administration of the two drugs cannot be excluded (see section 4.4).
Therefore, when administered in combination, blood pressure should be controlled considering, if necessary, a reduction in the dosage of nifedipine.
Quinupristin / Dalfopristin
Simultaneous administration of quinupristin / dalfopristin and nifedipine may result in elevated plasma concentrations of nifedipine (see section 4.4).
Following co-administration of the two drugs, blood pressure should be monitored and, if necessary, dose reduction of nifedipine should be considered.
Valproic acid
No formal studies have ever been conducted to evaluate the potential interaction between nifedipine and valproic acid. However, since the latter has been shown to increase plasma concentrations of nimodipine, a structurally similar calcium channel blocker, through enzyme inhibition, an increase in plasma concentrations, and therefore in efficacy, cannot be excluded, including for nifedipine (see section 4.4).
Cimetidine
Cimetidine, due to its inhibitory effect on the cytochrome P450 3A4 system, elevates the plasma levels of nifedipine and may potentiate its antihypertensive effect (see section 4.4).
Other studies
Cisapride
Simultaneous administration of cisapride and nifedipine may lead to increased plasma concentrations of nifedipine.
Antiepileptics inducing the cytochrome P450 3A4 system, such as phenytoin, carbamazepine and phenobarbital
Phenytoin induces the cytochrome P450 3A4 system. The simultaneous administration of phenytoin and nifedipine causes a reduction in the bioavailability and therefore in the efficacy of nifedipine.
If the two drugs are administered simultaneously, the clinical response to nifedipine should be monitored and, if necessary, its dose increased.
Similarly, if the nifedipine dose is increased during co-administration of the two drugs, a reduction in the nifedipine dose will be considered when treatment with phenytoin is discontinued.
No formal studies have ever been conducted to evaluate the potential interaction between nifedipine and carbamazepine or phenobarbital. However, since the latter have been shown to reduce the plasma concentrations of nimodipine, a structurally similar calcium channel blocker, through an enzyme induction process, a reduction in plasma concentrations, and therefore in efficacy, cannot be excluded. also for nifedipine.
Effects of nifedipine on other drugs
Antihypertensives
Nifedipine may accentuate the hypotensive effect of other antihypertensive agents administered in combination, such as:
- diuretics,
- β-blockers,
- ACE inhibitors,
- Angiotensin 1 receptor antagonists (AT-1),
- other calcium channel blockers,
- α-blockers,
- PDE5 inhibitors,
- α-methyldopa.
If associated with β-blockers, the patient should be carefully monitored as it is known that worsening of heart failure may occur in isolated cases.
Digoxin
The concomitant administration of nifedipine and digoxin may lead to an increase in plasma levels of digoxin, linked to a reduction in its clearance. As a precautionary measure, the patient should therefore be monitored for symptoms of digoxin overdose and, if necessary, to adjust the digoxin dosage based on his plasma levels.
Quinidine
In individual cases, reduced levels of quinidine or, after discontinuation of nifedipine, a marked increase in plasma levels of quinidine have been observed during concomitant administration of nifedipine and quinidine. For this reason, if nifedipine is used concomitantly or is discontinued, it is recommended that the plasma concentration of quinidine be controlled and, if necessary, its dosage adjusted.
Some authors have reported increases in plasma concentrations of nifedipine following co-administration of the two drugs, while others have not observed changes in the pharmacokinetics of nifedipine.
Therefore blood pressure should be carefully monitored if quinidine is combined with pre-existing nifedipine therapy: if necessary, the nifedipine dosage should be reduced.
Tacrolimus
Tacrolimus is metabolised via the cytochrome P450 3A4 system.
Recently published data indicate how, in individual cases, the dosage of tacrolimus can be reduced when it is administered concomitantly with nifedipine.
However, if the two drugs are administered in combination, the plasma concentrations of tacrolimus should be controlled, considering, if necessary, the dosage reduction of the latter.
Interactions with food
Grapefruit juice
Grapefruit juice inhibits the cytochrome P450 3A4 system.
The concomitant intake of grapefruit juice and nifedipine produces an increase in plasma concentrations of nifedipine and prolongs its action due to a reduced first pass metabolism or a decrease in clearance. Consequently, the antihypertensive effect may be increased. In case of regular consumption of grapefruit juice, this effect can last up to more than 3 days after the last intake.
Therefore, consumption of grapefruit / grapefruit juice should be avoided during treatment with nifedipine (see section 4.2).
Interactions that have been excluded
No effects on the pharmacokinetics of nifedipine have been demonstrated when administered concomitantly with: acetylsalicylic acid (the action on platelet aggregation and bleeding time is not modified for acetylsalicylic acid at a dose of 100 mg), benazepril, doxazosin, orlistat, pantoprazole, ranitidine, talinolol and triamterene hydrochlorothiazide.
No clinically relevant effects on the pharmacokinetics of nifedipine have been demonstrated when administered concomitantly with omeprazole or rosiglitazone.
Ajmaline
The concomitant administration of nifedipine and ajmaline has no effect on the metabolism of ajmaline.
Debrisoquine
Concomitant administration of nifedipine and debrisoquine has no effect on the metabolism of debrisoquine.
Candesartan cilexetil
Concomitant administration of nifedipine and candesartan cilexetil has no effect on the pharmacokinetics of the two drugs.
Irbesartan
Concomitant administration of nifedipine and irbesartan had no effect on the pharmacokinetics of irbesartan.
Other interactions
In the presence of nifedipine, the evaluation of the urinary values of vanil-mandelic acid carried out with the spectrophotometric method, can highlight false increases in the acid itself. These values are not, however, changed using the HPLC method.
04.6 Pregnancy and lactation
Pregnancy
Nifedipine is contraindicated in the first 20 weeks of pregnancy (see section 4.3).
There are no adequate and well-controlled studies in pregnant women.
Nifedipine has been shown to cause teratogenic effects in rats, mice and rabbits, such as digital anomalies, extremity malformations, cleft palate, sternal cleft, rib malformations. Digital anomalies and extremity malformations are likely the result of impaired uterine blood flow, but have also been observed in animals treated with nifedipine only after the period of organogenesis. Administration of the active substance has resulted in a variety of effects. toxic to the embryo, placenta and fetus such as poor fetal development (rat, mouse, rabbit), reduced placental size and chorionic villus hypotrophy (monkey), death of embryos and fetuses (rat, mouse, rabbit) and prolonged gestation / reduced neonatal survival (rat; not evaluated in other species). All the dosages associated with teratogenic, embryotoxic and foetotoxic effects were toxic for the maternal organism and, in any case, were many times higher than the maximum dosage indicated for human use.
Feeding time
Nifedipine passes into breast milk. Since there are no data on possible effects on the newborn, if treatment with nifedipine is required during this period, breastfeeding should be discontinued.
Fertilization in-vitro
In individual cases of fertilization in vitro calcium channel blockers such as nifedipine have been associated with reversible biochemical alterations in the apical part of the spermatozoon, with possible functional alteration of the sperm.
In cases of repeated failure of fertilization in vitro, not for any other reason, calcium channel blockers such as nifedipine should be considered as a possible cause.
04.7 Effects on ability to drive and use machines
Reactions to the drug, which vary in intensity from individual to individual, may impair the ability to drive or use machines. This is particularly true at the start of treatment, when changing the drug and in relation to the intake of alcoholic beverages.
04.8 Undesirable effects
Adverse drug reactions reported in clinical trials with nifedipine versus placebo are listed below and classified according to CIOMS III frequency categories (data from the clinical trial database: nifedipine n = 2.661; placebo n = 1.486; status: 22 February 2006 and data from ACTION study: nifedipine n = 3,825; placebo n = 3,840)
Adverse reactions classified as "common" were observed with a frequency of less than 3%, with the exception of edema (9.9%) and headache (3.9%).
The frequencies of adverse reactions reported with nifedipine products are summarized in the table below. Within each frequency class, undesirable effects are listed in order of decreasing severity. Frequencies are defined as: common (≥ 1/100,
In dialysis patients with malignant hypertension and hypovolemia, a marked drop in blood pressure may occur following vasodilation.
04.9 Overdose
Symptoms
In cases of severe nifedipine intoxication the following symptoms have been observed: disturbances of consciousness up to coma, drop in blood pressure, tachi / bradycardia-type cardiac rhythm disturbances, hyperglycemia, metabolic acidosis, hypoxia, cardiogenic shock with pulmonary edema.
Treatment of overdose
Regarding treatment, the elimination of the active substance and the stabilization of cardiovascular conditions have priority.
After oral ingestion, a thorough gastric lavage is indicated, associated, if necessary, with irrigation of the small intestine. In case of intoxication with nifedipine, elimination must be as complete as possible, including the small intestine, in order to prevent the " absorption of the active ingredient.
Hemodialysis is useless as nifedipine is not dialysable but plasmapheresis is recommended (due to the high protein binding and relatively low volume of distribution). Bradycardic heart rhythm disturbances can be treated with β-sympathomimetics, while the use of a temporary pacemaker should be considered for life-threatening alterations of this type.
Hypotension as a result of cardiogenic shock and arterial vasodilation can be treated with calcium (10-20 ml of 10% calcium gluconate solution to be administered slowly intravenously, possibly to be repeated).
As a result, the calcemia can reach the high values of the norm or slightly exceed them.
Should the effect of calcium on blood pressure prove insufficient, sympathomimetic vasoconstrictors, such as dopamine or noradrenaline, must also be administered, the dosage of which must be determined exclusively by the result obtained.
Infusion of fluids or plasma expanders must be carried out with caution due to the danger of cardiac overload.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: Calcium antagonists. Dihydropyridine derivatives.
ATC code: C08CA05.
Nifedipine is a 1,4-dihydropyridine calcium channel blocker. Calcium channel blockers reduce the intracellular transmembrane influx of calcium that occurs through slow calcium channels. Nifedipine acts particularly on myocardial and smooth muscle cells of the coronary arteries and peripheral resistance vessels.
At the cardiac level, nifedipine dilates the coronary arteries, in particular the large conductance vessels, and also the pathology-free wall segments in partially stenotic areas. Furthermore, nifedipine reduces the tone of the vascular smooth muscle to the same level, preventing its vasospasm. The final result of these actions is an increase in post-stenotic blood flow and consequently an increase in oxygen supply. At the same time, nifedipine reduces myocardial oxygen demand by reducing peripheral resistance (afterload). In chronic therapy, in the long term, nifedipine is also able to prevent the development of new coronary atherosclerotic lesions.
Nifedipine reduces the tone of the arteriolar smooth muscle, therefore, by reducing the increased peripheral resistance, it is able to lower blood pressure. At the beginning of therapy with nifedipine, a transient reflex increase in heart rate and therefore in cardiac output may occur. However this increase is not sufficient to compensate for vasodilation. Furthermore, nifedipine causes an increase in renal excretion of water and sodium both in treatment short-term rather than long-term. The hypotensive effect of nifedipine is particularly pronounced in hypertensive patients.
In subjects with Raynaud's syndrome, nifedipine is able to prevent or reduce the episodes of vasospasm in the fingers.
Pediatric population:
Limited information is available on nifedipine in comparison with other antihypertensive agents in both acute and long-term hypertension with different formulations in different strengths. The antihypertensive efficacy of nifedipine has been demonstrated, but recommended doses, long-term safety and cardiovascular efficacy have not been established.
There are no pediatric dosage forms available.
05.2 Pharmacokinetic properties
Absorption
After oral administration the absorption of nifedipine is rapid and almost complete.
The systemic bioavailability of orally administered nifedipine is 45-56% due to the first pass effect. absorption.
The table below shows the peak plasma concentrations (Cmax) and the corresponding times (Tmax).
Distribution
Nifedipine is 95% bound to plasma proteins (albumin). The distribution half-life after intravenous administration is 5 - 6 minutes.
Biotransformation
After oral administration, nifedipine is metabolised in the intestinal wall and in the liver mainly through oxidative processes. Oxidized metabolites do not exhibit pharmacological activity. The fundamental route of excretion of nifedipine in the oxidized form is the renal one, while only 5-15% is excreted via the bile with the faeces. The non-metabolised drug is found in trace amounts (less than 0.1%) in the urine.
Elimination
The elimination half-life is 1.7-3.4 hours. At the usual posology, no accumulation of the substance was found during prolonged treatment. In case of renal insufficiency, no substantial changes were observed compared to healthy volunteers.
In the presence of impaired hepatic function the elimination half-life is markedly lengthened and the total drug clearance is reduced. In more severe cases, a dose reduction may be necessary (see section 4.4).
05.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.
Acute toxicity: Acute toxicity has been studied in different animal models and the individual results are shown in the table below:
Subacute and Subchronic Toxicity: Daily oral administration to rats (50 mg / kg weight) and dog (100 mg / kg weight) for periods of 13 and 4 weeks, respectively, was tolerated without the appearance of toxic effects.
In parenteral (intravenous) administration the dog tolerated up to 0.1 mg / kg of weight per day for 6 days without damage. Daily intravenous administration of 2.5 mg / kg weight over a period of 3 weeks was tolerated by the rat without the appearance of signs of organ damage.
Chronic toxicity: the dog tolerated up to 100 mg / kg of weight per day, administered orally for a period of one year, without presenting toxic effects. Toxic effects appeared in rats with concentrations above 100 ppm in food (approximately 5-7 mg / kg body weight).
Carcinogenicity: A long-term study in rats (2 years) did not provide evidence of any carcinogenic effects of nifedipine.
Mutagenicity: the Ames test, the lethal dominance test and the micronucleus test were performed on the mouse to evaluate the mutagenic effect. It was not possible to detect any mutagenic effect of nifedipine.
Reproductive toxicology:
See section 4.6.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Glycerol, purified water, sodium saccharin, mint essence, macrogol 400.
Excipients making up the capsule: gelatin, glycerol 85%, titanium dioxide E 171, sunset yellow E 110.
06.2 Incompatibility
Not relevant
06.3 Period of validity
4 years
06.4 Special precautions for storage
Nifedipine is highly sensitive to light: therefore the capsules must not be broken because the protection from light is no longer ensured.
The tablets, contained in the special package, must be stored at a temperature not exceeding 30 ° C.
06.5 Nature of the immediate packaging and contents of the package
Opaque PVC / Aluminum and PP / Al blisters
Box of 50 soft capsules
06.6 Instructions for use and handling
Nifedipine, a photosensitive substance contained in the capsule, is substantially protected from light inside and outside the package.
However, the capsules should only be removed from the package immediately before use.
Adalat capsules should not be used after the expiration date.
07.0 MARKETING AUTHORIZATION HOLDER
BAYER S.p.A. - V.le Certosa, 130 Milan
08.0 MARKETING AUTHORIZATION NUMBER
AIC 023316021
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
First authorization: 28.04.76
Authorization renewal: June 2010
(on the market since May 1976)
10.0 DATE OF REVISION OF THE TEXT
Determination of 01/2012
