- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
Method of AdministrationFor oral useThese tablets should be swallowed whole with a glass of water and not bitten, broken up or chewed.
PosologyIt is recommended that each dose should be taken at approximately 24 hour intervals i.e. at the same time each day, preferably in the morning.Adults: In mild to moderate hypertension, the recommended initial dose is one 20mg tablet once daily. In severe hypertension and the prophylaxis of angina pectoris, the recommended initial dose is one 30mg tablet once daily. The dose may be adjusted to a maximum of 90mg once daily. Prophylactic anti-anginal efficacy is maintained when patients are switched from other calcium antagonists e.g. verapamil or diltiazem. When patients are switched, the recommended initial dose is 30mg nifedipine, once daily. Subsequent titration to a higher dosage should be according to clinical response.Older People: The pharmacokinetics of nifedipine may be altered in older people therefore, a lower maintenance dose may be necessary when treating older patients.Patients With Renal Impairment: Dosage adjustments should not be required for patients with impaired renal function.Patients With Hepatic Impairment: Nifedipine prolonged release tablets should not be administered to patients with impaired hepatic function.Paediatric population: The safety and efficacy of nifedipine in children under the age 18 years have not been established.Currently available data for the use of nifedipine in hypertension are described in section 5.1.Nifedipine is not recommended for use in children.Treatment with nifedipine may be continued long term.
Known InteractionsNifedipine should not be taken with grapefruit juice because bioavailability is increased.Cimetidine may potentiate the antihypertensive effect of nifedipine tablets if it is administered simultaneously.It is reported that serum quinidine levels have been reduced when it is used in combination with nifedipine, irrespective of the quinidine dose taken.The administration of nifedipine and digoxin concurrently may lead to reduced digoxin clearance and therefore, bring about an increase in the plasma digoxin level. Close monitoring of plasma digoxin levels should take place and, if necessary, a reduction in the dosage of digoxin.Phenytoin induces the cytochrome P450 3A4 system. When nifedipine is co-administered with phenytoin, nifedipine's bioavailability is reduced and consequently, its efficacy is weakened. In such cases, the clinical response to nifedipine should be monitored following concomitant administration and, if necessary, consideration should be given to increasing the nifedipine dose. If the nifedipine dose is increased during the co-administration of both drugs, consideration should be given to reducing the nifedipine dose when phenytoin therapy is discontinued.Diltiazem decreases the clearance of nifedipine and hence increases plasma nifedipine levels. Caution should be exercised when both drugs are given simultaneously. A reduction of nifedipine dose may be required when the two are used together.Nifedipine may falsely increase the spectrophotometric values of urinary vanillylmandelic acid. HPLC measurements are not affected.Nifedipine should not be administered concomitantly with rifampicin, as effective plasma levels of nifedipine may not be achieved as a result of enzyme induction.Simultaneous administration of cisapride and nifedipine or quinupristin/dalfopristin and nifedipine may lead to increased plasma concentration of nifedipine. Hence, the blood pressure may need to be monitored and a reduction in the nifedipine dose may be necessary.Nifedipine enhances the effect of non-polarising muscle relaxants.
Theoretical InteractionsNifedipine is metabolised via the cytochrome P450 3A4 system. Therefore, there are theoretical interactions with drugs such as erythromycin, ketoconazole, itraconazole, fluconazole, fluoxetine, indinavir, nelfinavir, ritonavir and saquinavir that are known to inhibit this enzyme system. Although no in vivo interaction studies with these drugs have been carried out, their co-administration with nifedipine in vitro, have shown increases in nifedipine plasma concentrations. Therefore, the blood pressure should be monitored and, if necessary, a reduction in the nifedipine dose should be considered.Similarly, the potential interaction between nifedipine and nefazodone has not been clinically investigated. Nefazodone is known to inhibit the cytochrome P450 3A4 mediated metabolism of other drugs and therefore, co-administration with nifedipine may increase the plasma concentrations of nifedipine. Again, monitoring of the blood pressure is advised when both drugs are simultaneously administrated with, if necessary, a reduction in the nifedipine dose. Tacrolimus is metabolised via the cytochrome P450 3A4 system. Upon co-administration with nifedipine, the plasma levels of tacrolimus should be monitored and, if necessary, consideration should be given to reducing the tacrolimus dose. Carbamazepine, phenobarbital or valproic acid have been shown to alter the plasma levels of a structurally similar calcium channel blocker, however, no interactive studies have been carried out with these drugs and nifedipine. A decrease (with carbamazepine or phenobarbital) or an increase (with valproic acid) in nifedipine plasma concentrations, leading to a change in efficacy, can therefore not be ruled out.
Drugs Shown Not to Interact With NifedipineAspirin, benazepril, candesartan cilexetil, debrisoquine, doxazosin, irbesartan, omeprazole, orlistat, pantoprazole, ranitidine, rosiglitazone and triamterene hydrochlorothiazide are drugs known not to affect the pharmacokinetics of nifedipine when they are administered concomitantly with nifedipine.
|Uncommon Side Effects ( > 0.1 % < 1 % )||Rare Side Effects ( > 0.01 % < 0.1 % )||Spontaneous Reports ( < 0.01 % )|
|Body as a Whole||abdominal pain, chest pain, leg pain, malaise||allergic reaction, chest pain substernal, chills, hypersensitivity-type jaundice, facial oedema fever||anaphylactic reaction, weight loss|
|Cardiovascular||hypotension, postural hypotension, syncope, tachycardia||cardiovascular disorder|
|Digestive||diarrhoea, dry mouth, dyspepsia, flatulence, nausea||anorexia, eructation, gastrointestinal disorder, gingivitis, gingival hyperplasia, vomiting||bezoar, dysphagia, oesophagitis, gum disorder, intestinal obstruction, intestinal ulcer|
|Hepatic||liver function test abnormalities, increase in GGT||increase in ALT, jaundice|
|Musculoskeletal||leg cramps||arthralgia, joint disorder, myalgia||muscle cramps|
|Neurological||insomnia, nervousness, paraesthesia, somnolence, vertigo||hyperaesthesia, sleep disorder, tremor, mood changes|
|Dermatological||pruritus, rash||angioedema, maculopapular, pustular and vesiculobullous rash, sweating, urticaria||purpura, exfoliative dermatitis, photosensitive dermatitis|
|Special Senses||abnormal vision, eye disorder, eye pain||blurred vision|
|Urogenital||nocturia, polyuria||dysuria, impotence|
SymptomsThere are few reports of nifedipine overdose and the symptoms are not necessarily dose-related. The most likely manifestations of overdose are severe hypotension due to vasodilatation, tachycardia or bradycardia.The metabolic disturbances may include hyperglycaemia, metabolic acidosis and hypo- or hyperkalaemia. The cardiac effects, which may occur, include heart block, AV dissociation and asystole and cardiogenic shock with pulmonary oedema.Other toxic effects include drowsiness, dizziness, confusion, nausea, vomiting, lethargy, flushing, hypoxia, unconsciousness and coma.
ManagementIn the treatment of overdose it is important to restore stable cardiovascular conditions as soon as possible and achieve total elimination of nifedipine.Gastric lavage and charcoal instillation may be of assistance if the patient is found early after the overdose. Gastric lavage may be necessary in combination with irrigation of the small intestine. Ipecacuanha should be given to children.To prevent the subsequent absorption of nifedipine, elimination must be complete, including from the small intestine.Activated charcoal should be given in 4 hourly doses of 25g for adults and 10g for children. The blood pressure, central arterial pressure, ECG, electrolytes, pulmonary wedge pressure and urea should be carefully monitored. Placing the patient in the supine position with the feet raised and the use of plasma expanders, as appropriate, should treat the hypotension resulting from cardiogenic shock and arterial vasodilatation. If these measures are ineffective, hypotension may be treated with 10ml to 20ml of 10% calcium gluconate, administered intravenously over a period of 5 to 10 minutes. If ineffective, the therapy can be continued, with ECG monitoring. Also, beta-sympathomimetics may be given eg. 0.2mg of isoprenaline by slow intravenous or 5μg per minute as a continuous infusion. If the blood pressure response is inadequate with calcium and isoprenaline, vasoconstricting sympathomimetics such as dopamine or noradrenaline should be administered. The patient's response should determine the dosage of these drugs.Bradycardia may be treated with atropine, beta-sympathomimetics or a temporary cardiac pacemaker.Additional fluid should be administered with caution to avoid cardiac overload.
|Anatomical Therapeutic Chemical (ATC) code:||C08C A05 Selective calcium channel blocker (dihydropyridine derivative), with mainly vascular effects|
Paediatric populationLimited information on comparison of nifedipine with other antihypertensives is available for both acute hypertension and long-term hypertension with different formulations in different dosages. Antihypertensive effects of nifedipine have been demonstrated but dose recommendations, long term safety and effect on cardiovascular outcome remain unestablished. Paediatric dosing forms are lacking.
General CharacteristicsNifedipine XL Tablets are formulated as prolonged release products. They are designed to control the release of nifedipine over twenty-four hours so that a clinical effect is achieved when the tablets are swallowed, once a day.The pharmacokinetic profile is characterised by low peak-trough fluctuation. Over twenty-four hours plasma concentration versus time profiles at steady state are plateau-like, rendering the Nifedipine XL Tablets suitable for once daily administration.
AbsorptionNifedipine is rapidly and almost completely absorbed from the gastrointestinal tract after oral administration. However, due to extensive hepatic first pass metabolism in the liver, the resultant bioavailability lies between 45% and 68%. The absorption rate is slightly changed when the tablets are taken after ingesting food but the extent of drug availability is not affected.
DistributionNifedipine is about 95% bound to plasma proteins.
MetabolismNifedipine is almost completely metabolised in the liver by oxidative and hydrolytic processes.
EliminationThe elimination half-life is 2 to 5 hours. About 70% to 80% of the administered dose of nifedipine is excreted via the kidneys, mostly as its active metabolites. The rest (5 % to 15 %) is excreted via the bile in the faeces. The non-metabolised drug substance is only found in traces (less than 1.0 %) in the urine.
Characteristics in Patients
Patients With Renal ImpairmentThere are no significant differences in the pharmacokinetics of nifedipine in patients with renal impairment and in healthy subjects. Therefore, dosage adjustments should not be required for patients with impaired renal function.
Patients With Hepatic ImpairmentNifedipine is primarily metabolised in the liver. The elimination half-life is markedly prolonged and there is a reduction in total clearance. Therefore, owing to the duration of action, nifedipine should not be administered to patients with reduced hepatic function.
|Mouse||454 ( 401 - 572 ) *||4.2 ( 3.8 - 4.6 ) *|
|Rat||1022 ( 950 - 1087 ) *||15.5 ( 13.7 - 17.5 ) *|
|Rabbit||250 - 500||2 - 3|
|Cat||~ 100||0.5 - 8|
|Dog||> 250||2 - 3|
Subacute & Subchronic Toxicity Studies ( in Rats and Dogs)Nifedipine doses of up to 50mg per Kg in rats and 100mg per kg in dogs p.o were tolerated without any damage when administered orally over periods of thirteen and four weeks, respectively. Nifedipine doses of 2.5mg per kg in rats and 0.1mg per kg in dogs were tolerated without any damage when administered intravenously over periods of three weeks and six days, respectively.
Chronic Toxicity Studies (in Rats and Dogs)Nifedipine doses of up to and including 100mg per kg in dogs p.o were tolerated without any damage when administered orally up to one year. In rats, toxic effect occurred at nifedipine concentrations above 100ppm in the feed (about 5mg to 7mg per kg body weight ).
Carcinogenic Studies (in Rats)Studies in rats over two years produced no evidence of carcinogenic effects caused by nifedipine.
Reproductive Studies (in Rats, Mice & Rabbits)Studies in rats, mice and rabbits maternally toxic doses of nifedipine induced some teratogenic and embryotoxic effects.
Mutagenic StudiesIn vivo and in vitro studies showed that nifedipine has no mutagenic properties.
In Tablet CorePovidone K30Lactose monohydrateCarbomer 974PSilica, colloidal anhydrous
In Tablet Core & CoatTalcHypromellose (E.464)Magnesium stearate
In Tablet CoatDimethylaminoethyl methacrylate-Butyl methacrylate-Methyl methacrylate copolymer Macrogol 4000Red iron oxide (E.172)Titanium dioxide (E.171)
Shelf Life of the Medicinal Product as Packaged for Sale24 monthsShelf Life After Dilution or ReconstitutionNot applicable
Shelf Life After First Opening the ContainerNot applicable
Chiesi Limited, 333 Styal Road, Manchester, M22 5LG
0800 009 2329
+44 (0) 161 488 5555