Summary of Product Characteristics Updated 15-Nov-2016 | Genus Pharmaceuticals
Tensipine MR 10One film-coated tablet contains 10mg nifedipine.
Tensipine MR 20One film-coated tablet contains 20mg nifedipine.For the full list of excipients, see section 6.1.
Tensipine MR 10Pink-grey lacquered, modified release tablets each containing 10mg nifedipine, one side marked TMR and the reverse side marked 10.
Tensipine MR 20Pink-grey lacquered, modified release tablets each containing 20mg nifedipine, one side marked TMR and the reverse side marked 20.
Method of AdministrationOral use.As a rule, tablets are swallowed whole with a little liquid, either with or without food. Tensipine MR should not be taken with grapefruit juice (see Section 4.5).
Dosage regimenThe recommended starting dose of Tensipine MR is 10mg every 12 hours swallowed with water with subsequent titration of dosage according to response. The dose may be adjusted to 40mg every 12 hours, to a maximum daily dose of 80mg.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 on special populations
Children and adolescentsThe 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.
Elderly patientsThe pharmacokinetics of nifedipine are altered in the elderly 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.
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 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 this 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 antiobiotics (e.g. erythromycin)No interaction studies have been carried out between nifedipine and macrolide antibiotics. Certain macrolide antibiotics are known to inhibit the 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).
Further Studies:− Diltiazem− 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 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 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-methyldopaWhen 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 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.Quinidine: When 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 nifedpine. If necessary, the dose of nifedipine should be decreased.Tacrolimus: Tacrolimus has been shown to be 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 interactions:
Grapefruit juiceGrapefruit 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 cause falsely increased spectrophotometric values of urinary vanillylmandelic acid. However, measurement with HPLC is unaffected.
PregnancyNifedipine is contra-indicated in pregnancy before week 20 (see section 4.3.) and should not be used during pregnancy unless the clinical condition of the woman requires treatment with nifedpine. Nifedipine should be reserved for women with severe hypertension who are unresponsive to standard therapy (see section 4.4).In animal studies, nifidepine has been shown to produce embryotoxicity, foetoxicity and teratogenicity (see section 5.3 Preclinical safety data).There are no adequate and 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 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.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 has 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. As there is no experience of possible effects on infants, breastfeeding should first be stopped if nifedipine treatment becomes necessary during the breastfeeding period.
FertilityIn 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.
|System Organ Class (MedDRA)||Common||Uncommon||Rare||Not Known|
|Blood and Lymphatic System Disorders||Agranulocytosis Leucopenia|
|Immune System Disorders||Allergic reaction Allergic oedema/ angioedema (inc. larynx oedema*)||Pruritus Urticaria Rash||Anaphylatic/ 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 (inc. peripheral oedema) Vasodilatation||Hypotension Syncope||Pulmonary oedema**|
|Respiratory, Thoracic, and Mediastinal Disorders||Nasal congestion Nosebleed||Dyspnea|
|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 Subcutanenous 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, tachycardiac / bradycardiac heart rhythm disturbances, hyperglycaemia, metabolic acidosis, hypoxia, cardiogenic shock with pulmonary oedema.
Management of OverdoseAs 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, 1g/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, after oral ingestion, consider thorough gastric lavage in adults within 1 hour of a potentially life-threatening overdose, if necessary in combination with irrigation of the small intestine3. Consider further doses of activated charcoal every 4 hours if a clinically significant amount of a sustained release preparation has been taken.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).Bradycardiac heart rhythm disturbances may be treated symptomatically with beta-sympathomimetics, and in life-threatening bradycardiac disturbances of heart rhythm, temporary cardiac pacemaker therapy can be advisable.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 slowly intraveneously over 5-10 minutes). As a result the serum calcium can reach the upper normal range to slightly elevated levels. 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 additionally administered. The dosage of these drugs is determined solely by the effect obtained / by the patient's response.Additional liquid or volume must be administered with caution because of the danger of overloading the heart.
ATC code: C08CA05Nifedipine is a specific and potent 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 myocardium and the smooth muscle cells of the coronary arteries and the peripheral resistance vessels. In hypertension, the main action of Tensipine MR is to cause peripheral vasodilatation and thus reduce peripheral resistance. In angina, Tensipine MR reduces peripheral and coronary vascular resistance, leading to an increase in coronary blood flow, cardiac output and stroke volume, whilst decreasing after-load. Additionally, nifedipine dilates submaximally both clear and atherosclerotic coronary arteries, thus protecting the heart against coronary artery spasm and improving perfusion to the ischaemic myocardium. Nifedipine reduces the frequency of painful attacks and the ischaemic ECG changes irrespective of the relative contribution from coronary artery spasm or atherosclerosis. Tensipine MR administered twice-daily provides 24-hour control of raised blood pressure. Tensipine MR causes reduction in blood pressure such that the percentage lowering is directly related to its initial level. In normotensive individuals, Tensipine MR has little or no effect on blood pressure.
Paediatric population:Limited 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.
AbsorptionAfter oral administration nifedipine is rapidly and almost completely absorbed. The systematic availability of orally administered nifedipine is 45 56% owing to a first pass effect. Maximum plasma and serum concentrations are reached at 1.5 to 4.2 hours with Tensipine MR (20mg tablets). Simultaneous food intake leads to delayed, but not reduced absorption.
DistributionNifedipine is about 95% bound to plasma protein (albumin). The distribution half-life after intraveneous administration was determined to be 5 to 6 minutes.
BiotransformationAfter oral administration nifedipine is metabolised 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 6 11 hours (Tensipine MR), because of delayed absorption. 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.
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 as 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 has been associated with a variety of embryotoxic, placentotoxic and fetotoxic effects, including stunted fetuses (rats, mice and 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 significantly high systematic exposure is achieved, however, all of the doses associated with the teratogenic, embryotoxic or fetotoxic effects in animals were maternally toxic and several times the recommended maximum dose for humans (see Section 4.6)
Tensipine MR 10PL 06831/0048
Tensipine MR 20PL 06831/0049
Tensipine MR 1019/02/2009
Tensipine MR 2023/02/2009
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+44 (0)1484 848164