Active ingredients: Nifedipine
Adalat Crono 20 mg modified release tablets
Adalat Crono 30 mg modified release tablets
Adalat Crono 60 mg modified release tablets
Why is Adalat Crono used? What is it for?
Adalat Crono contains nifedipine as the active substance, which belongs to the category of calcium channel blockers.
Adalat Crono is used to treat the following conditions:
- exertional angina (angina pectoris), which is severe chest pain in the region behind the breastbone due to insufficient blood and oxygen supply to the heart (usually following exertion). Nifedipine works by dilating the coronary arteries, thereby increasing the supply of blood and oxygen to the heart tissue. Furthermore, since it also acts in the peripheral vessels, it reduces the heart's need for oxygen.
- high blood pressure (arterial hypertension), as it causes the blood vessels to relax and increases the elimination of sodium and water. This results in a lowering of blood pressure, particularly marked in patients with high blood pressure.
Contraindications When Adalat Crono should not be used
Do not take Adalat Crono
- 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);
- if you are in cardiovascular shock (sudden drop in blood pressure);
- if you have a Kock's pocket ("deviation" after demolishing surgery on the colon and rectum);
- 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 Crono).
Precautions for use What you need to know before taking Adalat Crono
Talk to your doctor or pharmacist before taking Adalat Crono.
Take special care with Adalat Crono:
- If you have very low blood pressure (maximum pressure below 90 mm of mercury), if you have heart failure (weak heart) or severe aortic stenosis (narrowing of a heart valve);
- If you have severe narrowing of the gastrointestinal tract, as the tablet is made up of a non-absorbable shell, symptoms of intestinal blockage (intestinal obstruction) may arise. Exceptionally, these shells can give rise to the formation of bulky masses in the stomach, called bezoars, which cannot be eliminated through the intestine and sometimes require surgery. In individual cases, blockage symptoms also occurred in patients who had never experienced gastrointestinal complaints. If you undergo x-rays of the digestive tract with barium contrast, be aware that Adalat Crono can give images that can be falsely interpreted as polyps.
- 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 Crono.
- If you are pregnant, as the available information does not allow to exclude the possibility of undesirable effects on the unborn and newborn baby. For this reason, Adalat Crono should not be used in the first 20 weeks of pregnancy (see "Do not take Adalat Crono" and "Pregnancy and breastfeeding") and, in the following weeks, it can only be used after a very careful assessment of the possible risks. and the expected benefits and when other therapies are unsuitable or have not worked. Your doctor will then decide whether treatment with Adalat Crono is suitable for you. If you prescribe Adalat Crono, you are likely to have frequent monitoring of your pressure, particularly if it is given to you in combination with intravenous magnesium sulphate, due to the possibility of an excessive drop in blood pressure, which can harm both you and the fetus.
- If you are breastfeeding, as nifedipine passes into breast milk. For immediate release formulations it is recommended to delay breastfeeding or milk expression for 3 or 4 hours after taking the medicine in order to decrease the infant's exposure to nifedipine. Since there are no data on possible effects on the newborn, if treatment with nifedipine is required during this period, breastfeeding should be discontinued.
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
Adalat Crono is not recommended for use 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 modify the effect of Adalat Crono
Other medicines and Adalat Crono
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
As for Adalat Crono know that:
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 Crono together with medicines containing rifampicin (see "Do not take Adalat Crono").
- certain antibiotics belonging to the macrolide class, such as erythromycin;
- certain AIDS medicines, such as ritonavir, amprenavir, indinavir, nelfinavir or saquinavir;
- certain medicines for fungal infections, such as ketoconazole, itraconazole or 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:
- 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 arrhythmias), 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 weight loss) against diabetes), triamterene-hydrochlorothiazide (diuretic).
Adalat Crono with food and drink
Do not drink grapefruit juice while taking Adalat Crono, 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 and breastfeeding
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.
Do not take Adalat Crono if you are in the first 20 weeks of pregnancy or if you are breast-feeding (see "Do not take Adalat"). 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").
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.
Driving and using machines
Adalat Crono may cause dizziness or lightheadedness, particularly at the beginning of treatment or in combination with alcoholic beverages. If this affects you, do not drive or operate machinery.
Adalat Crono contains sodium
Adalat Crono tablets contain sodium. By taking the maximum daily dosage of 120 mg you can take up to 2 mmol of sodium per day. Take into consideration if you have reduced kidney function or if you are on a low sodium diet.
Dose, Method and Time of Administration How to use Adalat Crono: Posology
Always take this medicine exactly as your doctor or pharmacist has told you. If in doubt, consult your doctor or pharmacist.
The recommended dose is one 30 mg coated tablet once a day in the morning. The safety and efficacy of Adalat Crono under 18 years of age has not been established.
The dose, in the opinion of the physician, can be gradually increased to a maximum of 60 mg (one 60 mg coated tablet) in arterial hypertension or 120 mg (two 60 mg coated tablets) in angina pectoris, by taking the medicine once a day, in the morning. Your doctor may start treatment with one 20 mg tablet a day, or prescribe intermediate doses of 40 mg (20 + 20) or 50 mg (20 + 30).
Adalat Crono is for oral use. Swallow the tablet whole with some liquid. Do not chew or break the tablets. You can take Adalat Crono with or without food. Take the tablets out of the blister only at the time of taking.
In the Adalat Crono tablet, the medicine is contained within a non-absorbable shell, which slowly releases the substance to be absorbed. Once the process is complete, the empty tablet is discarded and can be seen in the stool.
Your doctor will decide how long treatment with Adalat Crono 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 liver 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 Crono
If you take more Adalat Cronus than you should
It is important to stick to the dose indicated by your doctor. If you have taken too many tablets by mistake, do not hesitate: ask your doctor what to do or contact the emergency room of the nearest hospital.
If you forget to take Adalat Crono
If you forget to take your medicine, take it as soon as you remember on the same day. If you happen to miss a day, take your normal dose the next day. Do not take a double dose to make up for a forgotten dose.
If you are not sure what to do, consult your doctor or pharmacist.
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 Crono
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) - itching,
- 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),
- bezoars (formation of bulky masses in the stomach),
- dysphagia (difficulty swallowing),
- intestinal obstruction (blocking the transit of intestinal contents),
- intestinal ulcer,
- 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).
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. 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 blister and carton. The expiry date refers to the last day of that month.
Store in the original package to protect the medicine from moisture.
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
What Adalat Crono contains
- The active ingredient is nifedipine. Each modified-release tablet contains:
Adalat Crono 20 mg modified release tablets 20 mg of nifedipine
Adalat Crono 30 mg modified release tablets 30 mg of nifedipine
Adalat Crono 60 mg modified release tablets 60 mg of nifedipine
- The other ingredients are:
Tablet core: polyethylene oxide, hypromellose, magnesium stearate, sodium chloride, red iron oxide (E172).
Coating: hypromellose, red iron oxide (E172), cellulose acetate, macrogols, hydroxypropyl cellulose, titanium dioxide, propylene glycol.
Description of the appearance of Adalat Crono and contents of the pack
Adalat Crono comes in the form of pink, round coated tablets, marked on one side with "ADALAT 20", "ADALAT 30" or "ADALAT 60".
Each pack contains 14 tablets in daily calendar blisters.
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
ADALAT CRONO MODIFIED RELEASE TABLETS
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Adalat Crono 20 mg modified release tablets
Each modified-release tablet contains: active ingredient 20 mg of nifedipine.
Adalat Crono 30 mg modified release tablets
Each modified-release tablet contains: active ingredient 30 mg of nifedipine.
Adalat Crono 60 mg modified release tablets
Each modified-release tablet contains: active ingredient 60 mg of nifedipine.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Modified-release tablet.
Adalat Crono 20 mg modified release tablets
Round, convex, pink-coated modified-release tablet with a laser-cut hole on one side.
Adalat Crono 30 mg modified release tablets
Round, convex, pink-coated modified-release tablet with a laser-cut hole on one side.
Adalat Crono 60 mg modified release tablets
Round, convex, pink-coated modified-release tablet with a laser-cut hole on one side.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
1. Treatment of the ischemic heart disease:
- chronic stable angina pectoris (exertional angina);
2. Treatment of the "hypertension.
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 addition, in relation to the clinical picture, the dose should be reached gradually.
Unless otherwise prescribed by a doctor, the following dosage guidelines apply to adults:
1. Ischemic heart disease
- chronic stable angina pectoris 1 tablet per day (angina from exertion)
The dose can be gradually increased, according to the individual needs of the patients, up to a maximum dose of 120 mg administered once daily in the morning.
2. Hypertension 1 tablet of Adalat Crono 30 mg per day
In some cases it may be appropriate to gradually increase the dose, according to individual needs, up to a maximum dosage of 60 mg administered once a day, in the morning.
In general, therapy should be started with 30 mg once daily.
A starting dose of 20 mg per day may be considered when clinically indicated.
Intermediate doses eg. 40 mg, 50 mg can be given by combinations, for example of 20 + 20 mg or 20 + 30 mg tablets.
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).
Any adjustments to higher or lower dosages should only be made under medical supervision.
Duration of treatment
The duration of treatment must be determined by the doctor.
How to use
The modified-release tablet should be swallowed whole with some liquid, regardless of mealtimes. Avoid grapefruit juice (see section 4.5).
Additional information for particular categories of patients
Children and adolescents
The safety and efficacy of Adalat Crono 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 altered in elderly subjects, these subjects may require lower doses of nifedipine than in younger patients.
Patients with impaired hepatic function
As nifedipine is almost completely metabolised in the intestinal wall and liver, careful control of the blood pressure situation and, in severe cases, a reduction in dosage 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
Adalat Crono must not be taken in cases of hypersensitivity to nifedipine or to any of the excipients (see sections 4.4 and 6.1).
Established (up to week 20) or presumed pregnancy and lactation (see section 4.6).
Adalat Crono should not be taken in cases of cardiovascular shock.
Adalat Crono should not be used in patients with Kock's pocket (ileostomy after proctocolectomy).
Nifedipine should not be used in combination with rifampicin because effective plasma levels of nifedipine are not achieved due to enzyme induction (see section 4.5).
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 those patients with severe aortic stenosis.
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 can harm both the mother and the fetus.
Nifedipine should not be used during pregnancy unless the clinical condition of the woman requires treatment with nifedipine. Treatment with nifedipine should be reserved for women with severe hypertension who are unresponsive to standard therapies (see section 4.6). The available information does not allow to exclude the possibility of undesirable effects on the unborn and neonate. Therefore, use in pregnancy after week 20 requires a very careful risk / benefit assessment and should only be considered if all other treatment options are not indicated or have proved ineffective.
The use of nifedipine is not recommended during lactation because nifedipine has been shown to be excreted in human milk and the effects of oral absorption of small amounts of nifedipine are unknown (see section 4.6).
In hypertensive emergency situations, such as eclampsia, the drug must be used under the responsibility and strict supervision of the physician.
In Adalat Crono the drug is contained within a non-absorbable shell that slowly releases the active ingredient to be absorbed. Once the process is complete, the empty tablet is discarded and can be seen in the stool.
As with other non-deformable materials (see section 6.6), caution should be exercised when administering Adalat Crono to patients with severe gastrointestinal tract stenosis as obstructive symptoms may arise. In very rare cases, the formation of bezoars may occur, spherical concretions of ingested foreign material that form in the stomach and fail to pass through the intestine, which may require surgical therapy. In individual cases, obstructive symptoms have been described even without anamnestic evidence. of gastrointestinal disorders In the course of radiological investigations with barium contrast, Adalat Crono can produce false positives (such as filling defects that can be interpreted as polyps).
In patients with impaired hepatic function, careful monitoring and, in severe cases, dose reduction may be necessary (see section 5.2).
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 therefore may result in increased 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.
Adalat Crono tablets contain sodium. Taking the maximum daily dose of 120 mg results in a maximum sodium intake of 2 mmol / day. This should therefore be taken into account in patients who require a controlled sodium intake.
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 efficacy. For this reason, the use of nifedipine in combination with rifampicin is contraindicated (see section 4.3). .
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 macrolides (e.g. erythromycin) 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 CYP3A4 inhibiting activity.
HIV protease inhibitors
A clinical study has not yet been conducted to investigate the potential interaction between nifedipine and certain HIV protease inhibitors (e.g. amprenavir, indinavir, nelfinavir, ritonavir or saquinavir). Drugs of this class are known to inhibit the cytochrome P450 3A4 system. Furthermore, they 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).
Azole antifungals
A specific study on the possible interaction between nifedipine and certain azole antifungals (e.g. ketoconazole, itraconazole or fluconazole) 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).
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).
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).
Quinupristin / dalfopristin
Simultaneous administration of quinupristin / dalfopristin and nifedipine may result in elevated plasma concentrations of nifedipine (see section 4.4).
Valproic acid
No formal studies have been conducted to evaluate the potential interaction between nifedipine and valproic acid. However, since the latter has been shown to increase the plasma concentrations of nimodipine, a structurally similar calcium channel blocker, through inhibition. enzymatic, an increase in plasma concentrations, and therefore efficacy, cannot be excluded, also 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
Co-administration of cisapride and nifedipine may lead to increased plasma levels 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 concomitant administration of the two drugs, a reduction in the nifedipine dose will be considered when phenytoin is discontinued.
No formal studies have 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 high-grade hypotension may occur. It is also known that worsening of heart failure can 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 that, in individual cases, the dosage of tacrolimus can be reduced when it is administered concomitantly with nifedipine.
However, when administered in combination, plasma concentrations of tacrolimus should be monitored, considering, if necessary, a reduction in the tacrolimus dose.
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 100 mg (for acetylsalicylic acid at a dose of 100 mg the action on platelet aggregation and bleeding time is not changed), benazepril, doxazosin, orlistat, pantoprazole, ranitidine, talinolol or 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
The evaluation of the urinary values of vanyl-mandelic acid carried out with the spectrophotometric method, in the presence of nifedipine, can show false increases in the acid itself. However, these values are not 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). Nifedipine should not be used during pregnancy unless the clinical condition of the woman requires treatment with nifedipine. Treatment with nifedipine should be reserved for women with severe hypertension who are unresponsive to standard therapies (see section 4.4).
There are no adequate and well-controlled studies in pregnant women.
There is insufficient information available to exclude adverse effects on the unborn child and neonate.
In animal studies, nifedipine has been shown to cause embryotoxicity, foetotoxicity and teratogenicity (see section 5.3).
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 dosages associated with teratogenic, embryotoxic or foetotoxic effects were toxic for the maternal organism and, in any case, were many times higher than the maximum dosage indicated for human use.
No specific prenatal risk has been identified from the available clinical evidence. Although an increase in perinatal asphyxia has been reported, caesarean deliveries in addition to prematurity and intrauterine growth retardation. It is unclear whether these cases are due to underlying hypertension, its treatment or a specific effect of the drug.
Feeding time
Nifedipine is excreted in breast milk. The concentration of nifedipine in milk is almost comparable to the serum concentration in the mother. For immediate release formulations, it is recommended to delay breastfeeding or milk expression for 3 or 4 hours after taking the drug in order to decrease the exposure of the infant to nifedipine (see section 4.4). As no data exist. on possible effects on the newborn, should nifedipine treatment be necessary during this period, breastfeeding should be discontinued.
Fertility
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 attributable to other reasons, calcium channel blockers such as nifedipine should be considered as a possible cause.
04.7 Effects on ability to drive and use machines
Drug reactions, which vary in intensity from individual to individual, may impair the ability to drive or use machines (see section 4.8). 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 (ADRs) 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.
Reporting of suspected adverse reactions.
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
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, if necessary, with irrigation of the small intestine.
Particularly in cases of intoxication with slow-release nifedipine formulations, such as Adalat Crono, elimination must be as complete as possible, including the small intestine, in order to prevent absorption of the active ingredient. Hemodialysis is useless as nifedipine is not dialyzable, 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 a temporary pacemaker should be considered for life-threatening changes 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.
Infusions of liquids or plasma expanders should be done with caution due to the risk of overloading the heart.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: selective calcium channel blockers with predominantly vascular effect. Dihydropyridine derivatives.
ATC code: C08CA05.
Nifedipine is a calcium channel blocker of the 1,4-dihydropyridine class. Calcium channel blockers reduce the intracellular trans-membrane flux of calcium ions through slow calcium channels. Nifedipine is particularly active on myocardial cells and on smooth muscle cells of coronary arteries and peripheral resistance vessels. At the cardiac level, nifedipine dilates the coronary arteries, especially the large-caliber conductance vessels, even in the normal segments of stenotic areas. Furthermore, nifedipine reduces the tone of the vascular smooth muscle of the coronary arteries and prevents their vasospasm. The final result is "increased post-stenotic blood flow and" increased oxygen supply. Parallel to this, nifedipine reduces O2 demand by decreasing peripheral resistance (afterload). In "long-term use. , nifedipine has also been shown to prevent the development of new atherosclerotic lesions in the coronary arteries.
Nifedipine reduces the tone of the vascular smooth muscle also of the arterioles, thus decreasing the peripheral resistance and, therefore, the arterial pressure. At the beginning of treatment with nifedipine, there may be a transient reflex increase in heart rate and, therefore, in cardiac output: this increase is not, however, able to compensate for vasodilation. Furthermore, nifedipine increases the excretion of sodium and water in both short-term and long-term use. The hypotensive effect of nifedipine is particularly pronounced in hypertensive patients.
Treatment with nifedipine in the INSIGHT study showed a reduction (in terms of absolute risk) in the risk of cardiovascular and cerebrovascular morbidity and mortality in hypertensive patients.
Another study, ACTION, a multicentre, randomized, placebo-controlled, double-blind study, involved 7665 patients with stable angina pectoris under the best available standard treatment. The study, which had a 5-year follow-up, evaluated the effects on clinical outcomes of nifedipine GITS in comparison with placebo.
In the primary efficacy endpoint (combined rate of death from any cause, acute myocardial infarction, refractory angina, new manifest heart failure, debilitating stroke and peripheral revascularization), no differences were found between patients allocated to nifedipine GITS (n = 3825 ) and those in the placebo group (n = 3840) (p = 0.54). In a predefined analysis on a subgroup of 3997 patients with angina and hypertension, Adalat Crono resulted in a significant 13% reduction in the endpoint. primary efficacy.
Adalat Crono was shown to be safe, as the primary safety endpoint (combined rate of death from any cause, acute myocardial infarction and debilitating stroke) was similar in the two treatment groups.
Adalat Crono had a positive effect on two of the three predefined secondary endpoints. The combined rate of death, major cardiovascular events, revascularization and coronary angiography (CAG) was reduced by 11% (p = 0.0012), mainly due to the marked decrease in the need for coronary angiography. There were 150 Fewer CAG as a first event in the nifedipine group compared to the placebo group. Any cardiovascular event it decreased by 9% (p = 0.027), mainly as a result of the reduced need for percutaneous coronary interventions and bypasses. Overall, there were 89 fewer first-event procedures in the nifedipine group than in the placebo group. Regarding the third secondary endpoint, "major cardiovascular event", no differences appeared between the two treatment groups (p = 0.26).
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
Adalat Crono tablets are formulated in such a way that nifedipine can be made available at an approximately constant rate over the course of 24 hours. Nifedipine is released from the tablet with zero order kinetics through a membrane-controlled osmotic pump process. The rate of release remains independent of both motility and pH of the gastrointestinal tract. Once ingested, the components of the tablet, biologically inert, remain intact along the gastrointestinal transit and are eliminated in the faeces as an insoluble shell.
Absorption
After oral administration, nifedipine is almost completely absorbed. The systemic availability of immediate-release oral formulations of nifedipine (Adalat capsules) is 45 - 56% for the first pass effect. At steady state, the bioavailability of Adalat Crono tablets varies between 68 and 86% of that of Adalat. capsules. Intake with food slightly changes the initial rate of absorption, but does not affect drug availability. The plasma concentration increases at a constant rate after a single dose of Adalat Crono and reaches a plateau after approximately 6 - 12 hours for the first. After multiple prolonged administration, the plasma concentration remains relatively constant around the plateau, exhibiting minimal fluctuations over the 24-hour interval between doses (with a peak-trough concentration ratio of 0.9 - 1 , 2 ng / ml) The following table shows, for Adalat Crono, the maximum peak plasma concentration values (Cmax) and the peak time (tmax) necessary to reach it:
* scarcely significant due to the almost constant trend in plasma concentration over time
Distribution
Nifedipine is 95% bound to plasma proteins (albumin). The distribution half-life after intravenous administration is between 5 and 6 minutes.
Biotransformation
After oral administration, nifedipine is metabolised in the enteric wall and liver mainly through oxidative processes; these metabolites show no pharmacodynamic activity. It is, therefore, excreted as metabolites mainly by the kidney and, for a variable amount of 5 - 15%, through the bile with the faeces. The unchanged active ingredient is found in the urine only in trace amounts (less than 0.1%).
Elimination
The terminal elimination half-life is between 1.7 and 3.4 hours for the conventional formulations (Adalat capsules) while for the Adalat Crono it does not represent a significant parameter since the plasma concentration remains almost constant thanks to the continuous release and subsequent absorption: only after the last administration does the plasma concentration progressively decline with an elimination half-life comparable to that of conventional formulations. In subjects with impaired renal function there were no significant changes in these parameters compared to healthy volunteers while clearance was reduced in patients with impaired hepatic function: in severe cases, therefore, a reduction of the dosage may be necessary (see section 4.4 ).
05.3 Preclinical safety data
Non-clinical data reveal no special hazard based on conventional studies of single and repeated dose toxicity, genotoxicity and carcinogenic potential.
Acute toxicity
Acute toxicity has been studied in different animal species and the individual results are shown in the following table:
* 95% confidence level
Subacute and subchronic toxicity
Daily oral administration to rats (50 mg / kg body weight) and dogs (100 mg / kg body weight) for a period of 13 and 4 weeks, respectively, was tolerated and free of toxic effects. After parenteral (intravenous) administration, dogs tolerated up to 0.1 mg / kg body weight per day without damage for 6 days, similarly to rats (2.5 mg / kg body weight per day) for a period of 3 weeks.
Chronic toxicity
Dogs tolerated, without toxic damage, up to 100 mg / kg of body weight per day, administered orally for over a year. In rats, toxic effects arose at concentrations of over 100 parts per million in the feed (corresponding to approximately 5 - 7 mg / kg body weight).
Carcinogenesis
A long-term study (2 years) in rats did not reveal any carcinogenic effects on nifedipine.
Mutagenicity
To evaluate the mutagenic effects, the Ames test, the Dominant-lethal test and the Micronucleus test were performed in mice. The onset of mutagenic effects on nifedipine was not highlighted.
Reproductive toxicology
See section 4.6.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Polyethylene oxide, hypromellose, magnesium stearate, sodium chloride, red iron oxide (E172), cellulose acetate, macrogols, hydroxypropylcellulose, titanium dioxide, propylene glycol.
06.2 Incompatibility
Not relevant.
06.3 Period of validity
3 years.
06.4 Special precautions for storage
Store in the original package to protect the medicine from moisture.
06.5 Nature of the immediate packaging and contents of the package
Daily calendar blister pack with:
1. PVC / PVDC / AL blister; (Adalat Crono 30 mg and 60 mg)
2. PA / ACLAR / AL blisters; (Adalat Crono 30 mg and 60 mg)
3. PP / AL blister; (Adalat Crono 20 mg, 30 mg and 60 mg)
Adalat Crono 20 mg modified release tablets - 14 tablets
Adalat Crono 30 mg modified release tablets - 14 tablets
Adalat Crono 60 mg modified release tablets - 14 tablets
Adalat Crono 20 mg modified release tablets - 28 tablets
Adalat Crono 30 mg modified release tablets - 28 tablets
Adalat Crono 60 mg modified release tablets - 28 tablets
06.6 Instructions for use and handling
The photosensitive active ingredient contained in Adalat Crono is protected from light both inside and outside the package. Since moisture protection is only guaranteed inside the package, the tablets should be removed from the blister only immediately before "use.
07.0 MARKETING AUTHORIZATION HOLDER
Bayer S.p.A. Viale Certosa 130 - Milan
08.0 MARKETING AUTHORIZATION NUMBER
9. 14 tablets
Adalat Crono 20 mg modified release tablets AIC 027980034
Adalat Crono 30 mg modified release tablets AIC 027980010
Adalat Crono 60 mg modified release tablets AIC 027980022
28 tablets
Adalat Crono 20 mg modified release tablets AIC 027980046
Adalat Crono 30 mg modified release tablets AIC 027980059
Adalat Crono 60 mg modified release tablets AIC 027980061
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
First authorization: 13.03.1992 (Adalat Crono 30 and 60)
First authorization: 18.08.1999 (Adalat Crono 20)
Renewal of the authorization: 13 March 2007
(on the market from: May 1992 tablets 30 and 60 mg on the market from: November 1999 tablets 20 mg)
10.0 DATE OF REVISION OF THE TEXT
AIFA determination of 04/2014
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