- 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
PosologyThe maximum total daily dose is 60 mg. The recommended starting dose is 5 mg every eight hours with subsequent titration of dose according to response permitting an increase to a maximum of 20 mg every eight hours. Co-administration 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 section 4.5).
Duration of treatmentTreatment may be continued indefinitely.
Additional information for special populations
Paediatric populationThe safety and efficacy of Adalat capsules in children below 18 years of age has not been established. Currently available data for the use of nifedipine in hypertension are described in section 5.1
Older people (>65 years)The pharmacokinetics of Adalat capsules are altered in the older people so that lower maintenance doses of nifedipine may be required.
Patients with hepatic impairmentNifedipine is metabolised primarily by the liver and therefore patients with liver dysfunction should be carefully monitored, and in severe cases, a dose reduction may be necessary.
Patients with renal impairmentBased on pharmacokinetic data, no dosage adjustment is required in patients with renal impairment (see section 5.2).
Method of administrationOral use. Adalat capsules should be swallowed whole with a little liquid, either with or without food. Adalat capsules should not be taken with grapefruit juice (see section 4.5).
Drugs that affect nifedipineNifedipine 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 Section 4.4). 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 co-administration with rifampicin, the bioavailability of nifedipine is distinctly reduced and thus its efficacy weakened. The use of nifedipine in combination with rifampicin is therefore contraindicated (see Section 4.3). Upon co-administration of known inhibitors of the cytochrome P450 3A4 system the blood pressure should be monitored and, if necessary, a reduction in the nifedipine dose considered (see Sections 4.2 and 4.4). In the majority of these cases, no formal studies to assess the potential for a drug interaction between nifedipine and the drug(s) listed have been undertaken, thus far.
Drugs increasing nifedipine exposure:• macrolide antibiotics (e.g., erythromycin)• anti-HIV protease inhibitors (e.g., ritonavir)• azole anti-mycotics (e.g., ketoconazole)• fluoxetine• nefazodone• quinupristin/dalfopristin• cisapride• valproic acid• cimetidine• diltiazem Upon co-administration of inducers of the cytochrome P450 3A4 system, the clinical response to nifedipine should be monitored and, if necessary, an increase in 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 is discontinued.
Drugs decreasing nifedipine exposure:• rifampicin (see above)• phenytoin• carbamazepine• phenobarbital
Effects of nifedipine on other drugsNifedipine may increase the blood pressure lowering effect of concomitant applied antihypertensives. When nifedipine is administered simultaneously with beta-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 the plasma digoxin level. The patient should therefore be subjected to precautionary checks for symptoms of digoxin overdosage and, if necessary, the glycoside dose should be reduced. Quinidine: Co-administration of nifedipine with quinidine may lower plasma quinidine levels, and after discontinuation of nifedipine, a distinct increase in plasma quinidine levels may be observed in individual cases. Consequently, when nifedipine is either additionally administered or discontinued, monitoring of the quinidine plasma concentration, and if necessary, adjustment of the quinidine dose are recommended. Blood pressure should be carefully monitored and, if necessary, the dose of nifedipine should be decreased. Tacrolimus: Tacrolimus is metabolised via the cytochrome P450 3A4 system. Published data 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 interactionsGrapefruit 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 of nifedipine may be increased. After regular intake of grapefruit juice, this effect may last for at least three days after the last ingestion of grapefruit juice. Ingestion of grapefruit/grapefruit juice is therefore to be avoided while taking nifedipine (see Section 4.2).
Other forms of interactionNifedipine may increase the spectrophotometric values of urinary vanillylmandelic acid falsely. However, HPLC measurements are unaffected.
PregnancyAdalat capsules should not be used during pregnancy unless the clinical condition of the woman requires treatment with nifedipine (see section 4.4). In animal studies, nifedipine has been shown to produce embryotoxicity, foetotoxicity and teratogenicity (see section 5.3). There are no adequate and well-controlled studies in pregnant women. 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 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. Acute pulmonary oedema has been observed when calcium channel blockers, among others nifedipine, have been used as a tocolytic agent during pregnancy (see section 4.8), especially in cases of multiple pregnancy (twins or more), with the intravenous route and/or concomitant use of beta-2 agonists.
Breast-feedingNifedipine is excreted in the breast milk. The nifedipine concentration in the milk is almost comparable with mother serum concentration. For immediate release formulations, it is proposed to delay breast-feeding or milk expression for 3 to 4 hours after drug administration to decrease the nifedipine exposure to the infant (see section 4.4).
FertilityIn single cases of in vitro fertilisation 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 fertilisation, and where no other explanation can be found, calcium antagonists like nifedipine should be considered as possible causes.
|System Organ Class (MedDRA)||Common||Uncommon||Rare||Not Known|
|Blood and Lymphatic System Disorders||Agranulocytosis Leucopenia|
|Immune System Disorders||Allergic reaction Allergic oedema / angioedema (incl. larynx oedema*)||Pruritus Urticaria Rash||Anaphylactic/ anaphylactoid reaction|
|Psychiatric Disorders||Anxiety reactions Sleep disorders|
|Metabolism and Nutrition Disorders||Hyperglycaemia|
|Nervous System Disorders||Headache||Vertigo Migraine Dizziness Tremor||Par-/Dysaesthesia||Hypoaesthesia Somnolence|
|Eye Disorders||Visual disturbances||Eye pain|
|Cardiac Disorders||Tachycardia Palpitations||Chest pain (Angina Pectoris)|
|Vascular Disorders||Oedema (incl. peripheral oedema) Vasodilatation||Hypotension Syncope|
|Respiratory, Thoracic, and Mediastinal Disorders||Nasal congestion Nosebleed||Dyspnoea Pulmonary oedema**|
|Gastrointestinal Disorders||Constipation||Gastrointestinal and abdominal pain Nausea Dyspepsia Flatulence Dry mouth||Gingival hyperplasia||Vomiting Gastroesophageal sphincter insufficiency|
|Hepatobiliary Disorders||Transient increase in liver enzymes||Jaundice|
|Skin and Subcutaneous Tissue Disorders||Erythema||Toxic Epidermal Necrolysis Photosensitivity allergic reaction Palpable purpura|
|Musculoskeletal and Connective Tissue Disorders||Muscle cramps Joint swelling||Arthralgia Myalgia|
|Renal and Urinary Disorders||Polyuria Dysuria|
|Reproductive System and Breast Disorders||Erectile dysfunction|
|General Disorders and Administration Site Conditions||Feeling unwell||Unspecific pain Chills|
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
SymptomsThe following symptoms are observed in cases of severe nifedipine intoxication: Disturbances of consciousness to the point of coma, a drop in blood pressure, tachycardia, bradycardia, hyperglycaemia, metabolic acidosis, hypoxia, cardiogenic shock with pulmonary oedema.
TreatmentAs far as treatment is concerned, elimination of nifedipine and the restoration of stable cardiovascular conditions have priority. Elimination must be as complete as possible, including the small intestine, to prevent the otherwise inevitable subsequent absorption of the active substance. The benefit of gastric decontamination is uncertain.1. Consider activated charcoal (50 g for adults, 1 g/kg for children) if the patient presents within 1 hour of ingestion of a potentially toxic amount. Although it may seem reasonable to assume that late administration of activated charcoal may be beneficial for sustained release (SR, MR) preparations there is no evidence to support this.2. Alternatively consider gastric lavage in adults within 1 hour of a potentially life-threatening overdose.3. Consider further doses of activated charcoal every 4 hours if a clinically significant amount of a sustained release preparation has been ingested with a single dose of an osmotic laxative (e.g. sorbitol, lactulose or magnesium sulfate).4. Asymptomatic patients should be observed for at least 4 hours after ingestion and for 12 hours if a sustained release preparation has been taken. Haemodialysis serves no purpose as nifedipine is not dialysable, but plasmapheresis is advisable (high plasma protein binding, relatively low volume of distribution). Hypotension as a result of cardiogenic shock and arterial vasodilatation can be treated with calcium (10-20 ml of a 10 % calcium gluconate solution administered intravenously over 5-10 minutes). If the effects are inadequate, the treatment can be continued, with ECG monitoring. If an insufficient increase in blood pressure is achieved with calcium, vasoconstricting sympathomimetics such as dopamine or noradrenaline should be administered. The dosage of these drugs should be determined by the patient's response. Symptomatic bradycardia may be treated with atropine, beta-sympathomimetics or a temporary cardiac pacemaker, as required. Additional fluids should be administered with caution to avoid cardiac overload.
AbsorptionAfter oral administration nifedipine is almost completely absorbed. The systemic availability of orally administered nifedipine immediate release formulation (Adalat capsules) is 45 56 % owing to a first pass effect. Maximum plasma and serum concentrations are reached at 30 to 60 minutes. Simultaneous food intake leads to delayed, but not reduced absorption.
DistributionNifedipine is about 95 % bound to plasma protein (albumin). The distribution half-life after intravenous administration has been determined to be 5 to 6 minutes.
BiotransformationAfter 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.
EliminationThe terminal elimination half-life is 1.7 to 3.4 hours. No accumulation of the substance after the usual dose was reported during long-term treatment. In cases of impaired kidney function no substantial changes have been detected in comparison with healthy volunteers. In cases of impaired liver function the elimination half-life is distinctly prolonged and the total clearance is reduced. A dose reduction may be necessary in severe cases (see Section 4.4).
Reproduction toxicologyNifedipine 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 the end of the organogenesis period. Nifedipine administration was associated with a variety of embryotoxic, placentotoxic and foetotoxic effects, including stunted foetuses (rats, mice, rabbits), small placentas and underdeveloped chorionic villi (monkeys), embryonic and foetal deaths (rats, mice, rabbits) and prolonged pregnancy/decreased neonatal survival (rats; not evaluated in other species). The risk to humans cannot be ruled out if a sufficiently high systemic exposure is achieved, however, all of the doses associated with the teratogenic, embryotoxic or foetotoxic effects in animals were maternally toxic and were several times the recommended maximum dose for humans.
|Date of first authorisation:||15 July 1977|
|Date of last renewal:||14 April 2004|
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