- 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
- 11. Legal category
Adipine MR 10One modified release tablet contains 10mg of nifedipine Excipient(s) with known effect: lactose monohydrate 39 mg
Adipine MR 20One modified release tablet contains 20mg of nifedipineExcipient(s) with known effect: lactose monohydrate 36.2 mgFor the full list of excipients, see section 6.1
PosologyThe recommended starting dose of Adipine MR is 10 mg every 12 hours swallowed with water with subsequent titration of dosage according to response. Adipine MR permit titration of the initial dosage, which may be adjusted to 40 mg every 12 hours, to a maximum daily dose of 80 mg.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).
Method of administrationOral use.As a rule, tablets are swallowed whole with a little liquid, either with or without food.Adipine MR should not be taken with grapefruit juice (see section 4.5).
Duration of treatmentTreatment may be continued indefinitely.
Additional information on special populations
Older people (> 65 years)The pharmacokinetics of nifedipine are altered in older people so that lower maintenance doses of nifedipine may be required compared to younger patients.
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).
Paediatric populationThe safety and efficacy of nifedipine 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.
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 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 contraindicated (see section 4.3).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 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.
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 section 4.4).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 section 4.4).
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 section 4.4).
FluoxetineA 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 section 4.4).
NefazodoneA 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 section 4.4).
Quinupristin / DalfopristinSimultaneous administration of quinupristin / dalfopristin and nifedipine may lead to increased plasma concentrations of nifedipine (see section 4.4).
Valproic acidNo 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 section 4.4).
CimetidineDue to its inhibition of cytochrome P450 3A4, cimetidine elevates the plasma concentrations of nifedipine and may potentiate the antihypertensive effect (see section 4.4).
CisaprideSimultaneous 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 phenobarbitonePhenytoin 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 in the nifedipine dose considered. If the dose of nifedipine is increased during coadministration 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 drugsNifedipine may increase the blood pressure lowering effect of concomitant applied antihypertensives, such as: • diuretics, • β-blockers, • ACE-inhibitors, • Angiotensin 1(AT1) receptor- antagonists, • other calcium antagonists, • α-adrenergic blocking agents, • PDE5 inhibitors, • α-methyldopa When nifedipine is administered simultaneously with ß-receptor blockers the patient should be carefully monitored, since deterioration of heart failure is also known to develop in isolated cases.
DigoxinThe simultaneous administration of nifedipine and digoxin may lead to reduced digoxin clearance and, hence, an increase in the 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.
QuinidineWhen nifedipine and quinidine have been administered simultaneously, lowered quinidine or, after discontinuation of nifedipine, a distinct increase in plasma concentrations of quinidine has 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 co-administration 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.
TacrolimusTacrolimus has been shown to be metabolised via the cytochrome P450 3A4 system. Data recently published indicates 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 inhibitsGrapefruit 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.
PregnancyNifedipine should not be used during pregnancy unless the clinical condition of the woman requires treatment with nifedipine. Nifedipine should be reserved for women with severe hypertension who are unresponsive to standard therapy (see section 4.4).There are no adequate well controlled studies in pregnant women.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.In animal studies, nifedipine has been shown to produce embryotoxicity, foetotoxicity and teratogenicity (see section 5.3).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.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 breastfeeding 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 oedma /angioedema (incl. larynx oedema1)||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||Nosebleed Nasal congestion||Dyspnoea Pulmonary oedema2|
|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.
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
|Test preparation:||Reference preparation:|
|Maximum steady-state plasma concentration (0-12 h) (Css,max1 ) (ng/ml):||36.3±12.1||39.8±15.9|
|Maximum steady-state plasma concentration (12-24 h) (Css,max2 ) (ng/ml):||39.1±15.4||50.3±19.6|
|Area under the concentration-time-curve (24h) (AUCss) (ng/ml*h):||394.3±165.7||435.6±194.6|
|Plateau time (0-24h) (h):||3.67±1.37||3.68±1.97|
|Peak-trough-fluctuation (0-12h) (PTF1) (%):||182.1±40.3||204.6±66.7|
|Peak-trough-fluctuation (12-24h) (PTF2) (%):||206.4±48.2||246.6±85.6|
|Values as mean values ± SD.|
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