Each prolonged-release tablet contains 30 mg nifedipine.
Excipients/Inactive Ingredients: Hypromellose, Polyethylene oxide, Magnesium stearate, Sodium chloride, Iron oxide red (E172/C.I.77491) Cellulose acetate, Polyethylene glycol 3350, Hydroxypropyl cellulose, Propylene glycol, Titanium dioxide (E171/C.I.77891).
Pharmacology: Pharmacodynamics: Nifedipine is a calcium antagonist of the 1,4-dihydropyridine type. Calcium antagonists reduce the transmembranal influx of calcium ions through the slow calcium channel into the cell. Nifedipine acts particularly on the cells of the myocardium and the smooth muscle cells of the coronary arteries and the peripheral resistance vessels.
Pharmacokinetics: Adalat LA tablets are formulated to provide nifedipine at an approximately constant rate over 24 hours. Nifedipine is released from the tablet at a zero-order rate by a membrane-controlled, osmotic push-pull process. The delivery rate is independent of gastrointestinal pH or motility. Upon swallowing, the biologically inert components of the tablet remain intact during 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 orally administered nifedipine immediate release formulations (nifedipine capsules) is 45 - 56 % owing to a first pass effect. At steady-state the bioavailability of Adalat LA tablets ranges from 68 - 86% relative to nifedipine capsules. Administration in the presence of food slightly alters the early rate of absorption, but does not influence the extent of drug availability.
Distribution: Nifedipine is about 95 % bound to plasma protein (albumin). The distribution half-life after intravenous administration has been determined to be 5 to 6 minutes.
Biotransformation: After oral administration nifedipine is metabolized in the gut wall and in the liver, primarily by oxidative processes. These metabolites show no pharmacodynamic activity.
Nifedipine is excreted in the form of its metabolites predominantly via the kidneys, and about 5 - 15 % via the bile in the faeces. The unchanged substance is recovered only in traces (below 0.1 %) in the urine.
Elimination: The terminal elimination half-life is 1.7 to 3.4 h in conventional formulations (nifedipine capsules). The terminal half-life after Adalat LA does not represent a meaningful parameter as a plateau-like plasma concentration is maintained during release from the tablets and absorption.
In cases of impaired kidney function no substantial changes have been detected in comparison with healthy volunteers.
In a study comparing the pharmacokinetics of nifedipine in patients with mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment with those in patients with normal liver function, oral clearance of nifedipine was reduced by on average 48% (Child Pugh A) and 72% (Child Pugh B). As a result AUC and Cmax of nifedipine increased on average by 93% and 64% (Child Pugh A) and by 253% and 171% (Child Pugh B), respectively, compared to patients with normal hepatic function. The pharmacokinetics of nifedipine has not been investigated in patients with severe hepatic impairment (see Precautions).
Toxicology: Preclinical Safety Data: Preclinical data reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity, genotoxicity and carcinogenic potential.
Reproduction toxicology: Nifedipine has been shown to produce teratogenic findings in rats, mice and rabbits, including digital anomalies, malformation of the extremities, cleft palates, cleft sternum and malformation of the ribs.
Digital anomalies and malformation of the extremities are possibly a result of compromised uterine blood flow, but have also been observed in animals treated with nifedipine solely after end of the organogenesis period.
Nifedipine administration was associated with a variety of embryotoxic, placentotoxic and fetotoxic effects, including stunted fetuses (rats, mice, rabbits), small placentas and underdeveloped chorionic villi (monkeys), embryonic and fetal deaths (rats, mice, rabbits) and prolonged pregnancy / decreased neonatal survival (rats; not evaluated in other species). All of the doses associated with the teratogenic, embryotoxic or fetotoxic effects in animals were maternally toxic at several times the recommended maximum dose for humans.
Treatment of coronary heart disease: Chronic stable angina pectoris (angina of effort).
Treatment of hypertension: Treatment of 6321 hypertensive patients with at least one additional risk factor followed over 3 to 4.8 years in a multi-national, randomised, double-blind, prospective study.
Nifedipine (Adalat LA) was shown to reduce cardiovascular and cerebrovascular events to a comparable degree as a standard diuretic combination (see Pharmacology: Pharmacodynamics under Actions).
Method of administration: Oral use.
Dosage regimen: As far as possible the treatment must be tailored to the needs of the individual.
Depending on the clinical picture in each case, the basic dose must be introduced gradually.
Unless otherwise prescribed, the following dosage guidelines are recommended for adults: For coronary heart disease: Chronic stable angina pectoris (angina of effort): 1 Adalat LA 30 mg tablet once daily (1 x 30 mg/day).
For hypertension: 1 Adalat LA 30 mg tablet once daily (1 x 30 mg/day).
In general therapy should be initiated with 30 mg once daily.
Depending on the severity of the disease and the patient's response the dose can be increased in stages up to 120 mg once daily.
Coadministration with CYP 3A4 inhibitors or CYP 3A4 inducers may result in the recommendation to adapt the nifedipine dose or not to use nifedipine at all (see Interactions).
Duration of Treatment: The attending doctor will determine the duration of use.
Administration: The tablets must not be chewed or broken up.
As a rule Adalat LA tablets are swallowed whole with a little liquid, irrespective of meal times. Grapefruit juice is to be avoided (see Interactions).
Additional information on special populations: Pediatric patients: The safety and efficacy of Adalat LA in children below 18 years has not been established.
Geriatric patients: Based on pharmacokinetic data for Adalat LA no dose adaptation in elderly people above 65 years is necessary.
Patients with hepatic impairment: In patients with mild, moderate or severe impaired liver function, careful monitoring and a dose reduction may be necessary. The pharmacokinetics of nifedipine has not been investigated in patients with severe hepatic impairment (see Precautions and Pharmacology: Pharmacokinetics under Actions).
Patients with renal impairment: Based on pharmacokinetic data no dosage adjustment is required in patients with renal impairment (see Pharmacology: Pharmacokinetics under Actions).
The tablets must not be chewed or broken up.
Symptoms: The following symptoms are observed in cases of severe nifedipine intoxication.
Disturbances of consciousness to the point of coma, a drop in blood pressure, tachycardiac / bradycardiac heart rhythm disturbances, hyperglycaemia, metabolic acidosis, hypoxia, cardiogenic shock with pulmonary oedema.
Management of Overdose: As far as treatment is concerned, elimination of the active substance and the restoration of stable cardiovascular conditions have priority.
After oral ingestion thorough gastric lavage is indicated, if necessary in combination with irrigation of the small intestine.
Particularly in cases of intoxication with slow-release products like Adalat LA elimination must be as complete as possible, including the small intestine, to prevent the otherwise inevitable subsequent absorption of the active substance.
Haemodialysis serves no purpose, as nifedipine is not dialysable, but plasmapheresis is advisable (high plasma protein binding, relatively low volume of distribution).
Bradycardiac heart rhythm disturbances may be treated symptomatically with β-sympathomimetics, and in life-threatening bradycardiac disturbances of heart rhythm temporary pacemaker therapy can be advisable.
Hypotension as a result of cardiogenic shock and arterial vasodilation can be treated with calcium (10 - 20 ml of a 10 % calcium gluconate solution administered slowly i.v. and repeated if necessary). As a result, the serum calcium can reach the upper normal range to slightly elevated levels. If an insufficient increase in blood pressure is achieved with calcium, vasoconstricting sympathomimetics such as dopamine or noradrenaline are additionally administered. The dosage of these drugs is determined solely by the effect obtained.
Additional liquid or volume must be administered with caution because of the danger of overloading the heart.
Adalat LA must not be used in cases of known hypersensitivity to nifedipine or to any of the excipients (see Excipients/Inactive Ingredients under Description).
Nifedipine is contraindicated in pregnancy before week 20 and during breastfeeding (see Use in Pregnancy & Lactation).
Adalat LA must not be used in cases of cardiovascular shock.
Adalat LA must not be used in patients with Kock pouch (ileostomy after proctocolectomy).
Nifedipine must not be used in combination with rifampicin because no efficient plasma levels of nifedipine may be obtained due to enzyme induction (see Interactions).
Care must be exercised in patients with very low blood pressure (severe hypotension with systolic pressure less than 90 mm Hg), in cases of manifest heart failure and in the case of severe aortic stenosis.
There are no safety and efficacy data from well-controlled studies in pregnant women.
Animal studies have shown a variety of embryotoxic, placentotoxic and fetotoxic effects (see Pharmacology: Toxicology: Preclinical safety data under Actions) when administered during and after the period of organogenesis.
From the clinical evidence available a specific prenatal risk has not been identified. Although an increase in perinatal asphyxia, caesarean delivery as well as prematurity and intrauterine growth retardation have been reported. It is unclear whether these reports are due to the underlying hypertension, its treatment or to a specific drug effect.
The available information is inadequate to rule out adverse drug effects on the unborn and newborn child. Therefore any use in pregnancy after week 20 requires a very careful individual risk benefit assessment and should only be considered if all other treatment options are either not indicated or have failed to be efficacious.
Careful monitoring of blood pressure must be exercised, also when administered nifedipine with i.v. magnesium sulfate, owing to the possibility of an excessive fall in blood pressure which could harm both mother and fetus.
As with other non-deformable material (see Instructions for use / handling under Cautions for Usage) care should be used when administering Adalat LA in patients with pre-existing severe gastrointestinal narrowing because obstructive symptoms may occur. Bezoars can occur in very rare cases and may require surgical intervention.
In single cases obstructive symptoms have been described without known history of gastrointestinal disorders.
When doing barium contrast X-ray Adalat LA may cause false positive effects (e.g. filling defects interpreted as polyp).
In patients with mild, moderate or severe impaired liver function careful monitoring and a dose reduction may be necessary. The pharmacokinetics of nifedipine has not been investigated in patients with severe hepatic impairment (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions). Therefore, nifedipine should be used with caution in patients with severe hepatic impairment.
Nifedipine is metabolised via the cytochrome P450 3A4 system. Drugs that are known to either inhibit or to induce this enzyme system may therefore alter the first pass or the clearance of nifedipine (see Interactions).
Drugs, which are inhibitors of the cytochrome P450 3A4 system and therefore may lead to increased plasma concentrations of nifedipine are, e.g.: macrolide antibiotics (e.g., erythromycin), anti-HIV protease inhibitors (e.g., ritonavir), azole antimycotics (e.g., ketoconazole), the antidepressants nefazodone and fluoxetine, quinupristin/dalfopristin, valproic acid, cimetidine.
Upon co-administration with these drugs, the blood pressure should be monitored and, if necessary, a reduction of the nifedipine dose should be considered.
For use in special populations see Dosage & Administration.
Effects on ability to drive and use machines: Reactions to the drug, which vary in intensity from individual to individual, can impair the ability to drive or to operate machinery (see Adverse Reactions). This applies particularly at the start of the treatment, on changing the medication and in combination with alcohol.
Pregnancy: Nifedipine is contraindicated in pregnancy before week 20 (see Contraindications). There are no adequate and well controlled studies in pregnant women.
In animal studies nifedipine has been shown to produce embryotoxicity, fetotoxicity and teratogenicity (see Pharmacology: Toxicology: Preclinical safety data under Actions).
Lactation: Nifedipine passes into the breast milk. As there is no experience of possible effects on infants, breastfeeding should first be stopped if nifedipine treatment becomes necessary during the breastfeeding period.
In-vitro fertilization: In single cases of in vitro fertilization calcium antagonists like nifedipine have been associated with reversible biochemical changes in the spermatozoa's head section that may result in impaired sperm function. In those men who are repeatedly unsuccessful in fathering a child by in vitro fertilization, and where no other explanation can be found, calcium antagonists like nifedipine should be considered as possible causes.
Adverse drug reactions (ADRs) based on placebo-controlled studies with nifedipine sorted by CIOMS III categories of frequency (clinical trial data base: nifedipine n = 2,661; placebo n = 1,486; status: 22 Feb 2006 and the ACTION study: nifedipine n = 3,825; placebo n = 3,840) are listed as follows: ADRs listed under "common" were observed with a frequency below 3% with the exception of oedema (9.9%) and headache (3.9%).
The frequencies of ADRs reported with nifedipine containing products are summarised in the table as follows. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as common (≥1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100) and rare (≥ 1/10,000 to < 1/1,000). The ADRs identified only during the ongoing postmarketing surveillance, and for which a frequency could not be estimated, are listed under "Not known". (See table.)
Click on icon to see table/diagram/image
In dialysis patients with malignant hypertension and hypovolaemia a distinct fall in blood pressure can occur as a result of vasodilation.
Drugs that affect nifedipine: Nifedipine is metabolised via the cytochrome P450 3A4 system, located both in the intestinal mucosa and in the liver. Drugs that are known to either inhibit or to induce this enzyme system may therefore alter the first pass (after oral administration) or the clearance of nifedipine (see Precautions).
The extent as well as the duration of interactions should be taken into account when administering nifedipine together with the following drugs: Rifampicin: Rifampicin strongly induces the cytochrome P450 3A4 system. Upon coadministration with rifampicin, the bioavailability of nifedipine is distinctly reduced and thus its efficacy weakened. The use of nifedipine in combination with rifampicin is therefore contra-indicated (see Contraindications).
Upon co-administration of the following weak to moderate inhibitors of the cytochrome P450 3A4 system the blood pressure should be monitored and, if necessary, a reduction in the nifedipine dose considered (see Dosage & Administration).
Macrolide antibiotics (e.g., erythromycin): No interaction studies have been carried out between nifedipine and macrolide antibiotics. Certain macrolide antibiotics are known to inhibit the cytochrome P450 3A4 mediated metabolism of other drugs. Therefore the potential for an increase of nifedipine plasma concentrations upon co-administration of both drugs cannot be excluded (see Precautions).
Azithromycin, although structurally related to the class of macrolide antibiotics is void of CYP3A4 inhibition.
Anti-HIV protease inhibitors (e.g., ritonavir): A clinical study investigating the potential of a drug interaction between nifedipine and certain anti-HIV protease inhibitors has not yet been performed. Drugs of this class are known to inhibit the cytochrome P450 3A4 system. In addition, drugs of this class have been shown to inhibit in vitro the cytochrome P450 3A4 mediated metabolism of nifedipine. When administered together with nifedipine, a substantial increase in plasma concentrations of nifedipine due to a decreased first pass metabolism and a decreased elimination cannot be excluded (see Precautions).
Azole anti-mycotics (e.g., ketoconazole): A formal interaction study investigating the potential of a drug interaction between nifedipine and certain azole anti-mycotics has not yet been performed. Drugs of this class are known to inhibit the cytochrome P450 3A4 system. When administered orally together with nifedipine, a substantial increase in systemic bioavailability of nifedipine due to a decreased first pass metabolism cannot be excluded (see Precautions).
Fluoxetine: A clinical study investigating the potential of a drug interaction between nifedipine and fluoxetine has not yet been performed. Fluoxetine has been shown to inhibit in vitro the cytochrome P450 3A4 mediated metabolism of nifedipine. Therefore an increase of nifedipine plasma concentrations upon co-administration of both drugs cannot be excluded (see Precautions).
Nefazodone: A clinical study investigating the potential of a drug interaction between nifedipine and nefazodone has not yet been performed. Nefazodone is known to inhibit the cytochrome P450 3A4 mediated metabolism of other drugs. Therefore an increase of nifedipine plasma concentrations upon co-administration of both drugs cannot be excluded (see Precautions).
Quinupristin / Dalfopristin: Simultaneous administration of quinupristin / dalfopristin and nifedipine may lead to increased plasma concentrations of nifedipine (see Precautions).
Valproic acid: No formal studies have been performed to investigate the potential interaction between nifedipine and valproic acid. As valproic acid has been shown to increase the plasma concentrations of the structurally similar calcium channel blocker nimodipine due to enzyme inhibition, an increase in nifedipine plasma concentrations and hence an increase in efficacy cannot be excluded (see Precautions).
Cimetidine: Due to its inhibition of cytochrome P450 3A4, cimetidine elevates the plasma concentrations of nifedipine and may potentiate the antihypertensive effect (see Precautions).
Further studies: Cisapride: Simultaneous administration of cisapride and nifedipine may lead to increased plasma concentrations of nifedipine.
Cytochrome P450 3A4 system-inducing anti-epileptic drugs, such as phenytoin, carbamazepine and phenobarbitone: Phenytoin induces the cytochrome P450 3A4 system. Upon co-administration with phenytoin, the bioavailability of nifedipine is reduced and thus its efficacy weakened. When both drugs are concomitantly administered, the clinical response to nifedipine should be monitored and, if necessary, an increase of the nifedipine dose considered. If the dose of nifedipine is increased during co-administration of both drugs, a reduction of the nifedipine dose should be considered when the treatment with phenytoin is discontinued.
No formal studies have been performed to investigate the potential interaction between nifedipine and carbamazepine or phenobarbitone. As both drugs have been shown to reduce the plasma concentrations of the structurally similar calcium channel blocker nimodipine due to enzyme induction, a decrease in nifedipine plasma concentrations and hence a decrease in efficacy cannot be excluded.
Effects of nifedipine on other drugs: Blood pressure lowering drugs: Nifedipine may increase the blood pressure lowering effect of concomitant applied antihypertensives, such as: diuretics, β-blockers, ACE-inhibitors, Angiotensin II (AT1) receptor-antagonists, other calcium antagonists, α-adrenergic blocking agents, PDE5 inhibitors, α-methyldopa.
When nifedipine is administered simultaneously with β-receptor blockers the patient should be carefully monitored, since deterioration of heart failure is also known to develop in isolated cases.
Digoxin: The simultaneous administration of nifedipine and digoxin may lead to reduced digoxin clearance and hence an increase in plasma concentrations of digoxin. The patient should therefore be checked for symptoms of digoxin overdosage as a precaution and, if necessary, the glycoside dose should be reduced taking account of the plasma concentration of digoxin.
Quinidine: When nifedipine and quinidine have been administered simultaneously, lowered quinidine or, after discontinuation of nifedipine, a distinct increase in plasma concentrations of quinidine have been observed in individual cases. For this reason, when nifedipine is either additionally administered or discontinued, monitoring of the quinidine plasma concentration and, if necessary, adjustment of the quinidine dose are recommended. Some authors reported increased plasma concentrations of nifedipine upon coadministration of both drugs, while others did not observe an alteration in the pharmacokinetics of nifedipine.
Therefore, the blood pressure should be carefully monitored, if quinidine is added to an existing therapy with nifedipine. If necessary, the dose of nifedipine should be decreased.
Tacrolimus: Tacrolimus has been shown to be metabolised via the cytochrome P450 3A4 system.
Data recently published indicate that the dose of tacrolimus administered simultaneously with nifedipine may be reduced in individual cases. Upon co-administration of both drugs the tacrolimus plasma concentrations should be monitored and, if necessary, a reduction in the tacrolimus dose considered.
Drug-food interactions: Grapefruit juice: Grapefruit juice inhibits the cytochrome P450 3A4 system. Administration of nifedipine together with grapefruit juice thus results in elevated plasma concentrations and prolonged action of nifedipine due to a decreased first pass metabolism or reduced clearance. As a consequence, the blood pressure lowering effect may be increased. After regular intake of grapefruit juice this effect may last for at least 3 days after the last ingestion of grapefruit juice.
Ingestion of grapefruit / grapefruit juice is therefore to be avoided while taking nifedipine (see Dosage & Administration).
Other forms of interaction: Nifedipine may cause falsely increased spectrophotometric values of urinary vanillyl-mandelic acid. However, measurement with HPLC is unaffected.
Instructions for use / handling: In Adalat LA the medication is contained within a non-absorbable shell that slowly releases the drug for the body to absorb. When this process is completed, the empty tablet is eliminated from the body and may be noticed in the stool.
The light-sensitive active substance contained in Adalat LA is protected from light inside and outside its packaging. The tablets must be protected from humidity and must therefore only be removed from the foil immediately before use.
C08CA05 - nifedipine ; Belongs to the class of dihydropyridine derivative selective calcium-channel blockers with mainly vascular effects. Used in the treatment of cardiovascular diseases.
Adalat LA PR tab 30 mg