Nifedipine Capsules 5 Mg
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
NIFEDIPINE CAPSULES 5mg
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains 5mg Nifedipine Ph Eur
3 PHARMACEUTICAL FORM
Orange soft gelatin capsules.
4. CLINICAL PARTICULARS
4.1 Therapeutic Indications
1) Prophylaxis of chronic stable angina pectoris.
2) Treatment of Raynaud's phenomenon and hypertension.
4.2 Posology and method of administration
Posology
The capsules should be administered with a little fluid during or after food.
Adults: The recommended starting dose is 5mg every 8 hours with subsequent titration of dosage according to response. The dosage may be adjusted to a maximum of 20mg every 8 hours.
Elderly: The pharmacokinetics of nifedipine are altered in the elderly so that lower maintenance doses of nifedipine may be required compared to younger patients.
Use in hepatic dysfunction: Nifedipine is metabolised primarily by the liver and therefore patients with liver dysfunction should be carefully monitored. Use in renal impairment: Patients with renal impairment should not require adjustment of dosage.
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
Method of administration For oral administration.
4.3 Contraindications
• Nifedipine capsules must not be used in cases of known hypersensitivity to nifedipine or to any of the excipients (see section 4.4, see section 6.1).
• Nifedipine capsules must not be used in cases of cardiovascular shock
• Immediate release nifedipine is contraindicated in unstable angina pectoris and after acute myocardial infarction within the first 4 weeks.
• Nifedipine capsules must not be used in combination with rifampicin because no efficient plasma levels of nifedipine may be obtained due to enzyme induction (see Section 4.5).
4.4 Special Warnings and Precautions for Use
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.
Treatment with immediate release nifedipine may induce an exaggerated fall in blood pressure with reflex tachycardia, which could result in cardiovascular complications.
As with other vasoactive substances, angina pectoris may very rarely occur (data from spontaneous reports) with immediate release nifedipine, especially at the start of the treatment. Data from clinical studies confirm that the occurrence of angina pectoris attacks is uncommon.
In patients suffering from angina pectoris an increase in frequency, duration and severity of angina pectoris attacks may occur, especially at the start of the treatment.
The occurrence of myocardial infarction has been described in isolated cases, although it was not possible to distinguish this from the natural course of the underlying disease.
Nifedipine 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 4.6).
Nifedipine is not recommended for use during breastfeeding because nifedipine has been reported to be excreted in human milk and the effects of oral absorption of small amounts of nifedipine are not known (see section 4.6).
Careful monitoring of blood pressure must be exercised, also when administering nifedipine with i.v. magnesium sulphate, owing to the possibility of an excessive fall in blood pressure which could harm both mother and foetus.
In patients with impaired liver function, careful monitoring, and in severe cases a dose reduction, may be necessary.
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 section 4.5).
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 Section 4.2.
4.5 Interactions with other Medicaments and other forms of Interaction 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 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).
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).
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 coadministration of both drugs cannot be excluded (see section 4.4).
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 coadministration of both drugs cannot be excluded (see section 4.4).
Quinupristin / Dalfopristin
Simultaneous administration of quinupristin / dalfopristin and nifedipine may lead to increased plasma concentrations of nifedipine (see section 4.4).
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 section 4.4).
Cimetidine
Due 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
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,
- P-blockers,
- ACE-inhibitors,
- Angiotensin 1(AT1) receptor- antagonists,
- other calcium antagonists,
- a-adrenergic blocking agents,
- PDE5 inhibitors,
- a-methyldopa
When nifedipine is administered simultaneously with P-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 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 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 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 interaction:
Nifedipine may cause falsely increased spectrophotometric values of urinary vanillylmandelic acid. However, HPLC measurements are unaffected.
4.6 Pregnancy and Lactation Pregnancy
Nifedipine 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).
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.
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.
Breast-feeding
Nifedipine 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).
Fertility
In 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.
4.7 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 section 4.8). This applies particularly at the start of treatment, on changing the medication and in combination with alcohol.
4.8 Undesirable Effects
dverse 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 below: 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 below. 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”.
|
System Organ Class (MedDRA) |
Common |
Uncommon |
Rare |
Not known |
|
Blood and lymphatic system disorders |
Agranulocytosis Leukopenia | |||
|
Immune system disorders |
Allergic reaction Allergic oedema / angioedema (incl. larynx oedema ) |
Pruritus Urticaria Rash |
Anaphylactic/ anaphylactoid reactio | |
|
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) |
|
System Organ Class (MedDRA) |
Common |
Uncommon |
Rare |
Not known |
|
Vascular disorders |
Oedema (incl. peripheral oedema) Vasodilatation |
Hypotension Syncope | ||
|
Respiratory, thoracic, and mediastinal disorders |
Nosebleed Nasal congestion |
Dyspnea, Pulmonary oedema** | ||
|
Gastrointestinal disorders |
Constipation |
Gastrointestinal and abdominal pain Nausea Dyspepsia Flatulence Dry mouth |
Gingival hyperplasia |
Vomiting Gastrooesophageal sphincter insufficienc |
|
Hepatobiliary disorders |
Transient increase in liver enzymes |
Jaundice | ||
|
Skin and subcutaneous tissue disorders |
Erythema |
Toxic Epidermal Necrolysis Photosensitivity aller reaction Palpable purpura | ||
|
Musculoskeletal and connective tissue disorders |
Muscle cramps Joint swelling |
Arthralgia Myalgia | ||
|
Renal and urinary disorders |
Polyuria Dysuria | |||
|
Reproductive |
Erectile |
|
System Organ Class (MedDRA) |
Common |
Uncommon |
Rare |
Not known |
|
system and breast disorders |
dysfunction | |||
|
General disorders and administration site conditions |
Feeling unwell |
Unspecific pain Chills |
may result in life threatening outcome ** Cases have been reported when used as tocolytic during pregnancy (see section 4.6).
In dialysis patients with malignant hypertension and hypovolaemia a distinct fall in blood pressure can occur as a result of vasodilation
Reporting of suspected adverse reactions
Reporting 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.
4.9 Overdose 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 nifedipine 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.
In case of intoxication with nifedipine elimination must be as complete as possible, including the small intestine, to prevent 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).
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 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 should be administered. The dosage of these drugs is determined solely by the effect obtained.
Bradycardiac heart rhythm disturbances may be treated symptomatically with beta-sympathomimetics, and in life-threatening bradycardiac disturbances of heart rhythm temporary pacemaker therapy can be advisable
Additional liquid or volume must be administered with caution because of the danger of overloading the heart.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
ATC Code: C08C A05
Nifedipine is a calcium-channel blocking agent.
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. As a specific and potent calcium antagonist, nifedipine acts particularly on the cells of the myocardium and the smooth muscle cells of the coronary arteries and the peripheral resistance vessels. The main action of Nifedipine capsules is to relax arterial smooth muscle both in the coronary and peripheral circulation.
In angina pectoris, nifedipine capsules relax peripheral arteries so reducing the load on the left ventricle. Additionally, nifedipine dilates submaximally both clear and pre-stenotic, stenotic and post-stenotic coronary arteries, thus protecting the heart against coronary artery spasm and improving perfusion to the ischaemic myocardium.
Nifedipine capsules reduce the frequency of painful attacks and ischaemic ECG changes, irrespective of the relative contribution from coronary artery spasm or atherosclerosis.
Nifedipine causes a reduction in blood pressure such that the percentage lowering is directly related to its initial height. In normotensive individuals, nifedipine 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.
5.2 Pharmacokinetic properties
Absorption
After oral administration nifedipine is almost completely absorbed. The systemic availability of orally administered nifedipine immediate release formulation (Nifedipine 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.
Distribution
Nifedipine is about 95 % bound to plasma protein (albumin). The distribution halflife 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 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).
5.3 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 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.
6. PHARMACEUTICAL PARTICULARS
6.1.
List of Excipients
Polyethylene glycol Glycerol Peppermint oil
The capsule contains:
Glycerol
Gelatin
Sunset yellow (El10)
Titanium dioxide (E171)
The printing ink contains:
Propylene glycol Iron oxide black (E172)
Polyvinyl acetate phthalate Macrogol 400 Ammonium hydroxide
6.2. Incompatibilities
None known.
6.3. Shelf-Life
Shelf-life
Two years from the date of manufacture.
Shelf-life after dilution/reconstitution Not applicable.
Shelf-life after first opening Not applicable.
6.4. Special Precautions for Storage
Store below 30°C in a dry place.
Protect from light.
The product containers are rigid injection moulded polypropylene or injection blow-moulded polyethylene containers with polyfoam wad or polyethylene ullage filler and snap-on polyethylene lids; in case any supply difficulties should arise the alternative is amber glass containers with screw caps and polyfoam wad or cotton wool.
The product may also be supplied in blister packs in cartons:
a) Carton: Printed carton manufactured from white folding box board.
b) Blister pack: (i) 250pm white rigid PVC with a 66g/M2 PVDC coating on one side.
(ii) Surface printed 20pm hard temper aluminium foil with 5-6g/M2 PVC and PVDC compatible heat seal lacquer on the reverse side.
Pack sizes: 28s, 30s, 50s, 56s, 60s, 84s, 90s, 100s, 112s, 120s, 168s, 180s, 250s, 500s,
1000s.
Product may also be supplied in bulk packs in polybags contained in tins, skillets or polybuckets filled with suitable cushioning material.
Maximum size of bulk packs: 50,000.
6.6. Instructions for Use/Handling
Not applicable.
7 MARKETING AUTHORISATION HOLDER
Actavis UK Limited (Trading style: Actavis) Whiddon Valley BARNSTAPLE N Devon EX32 8NS
8. MARKETING AUTHORISATION NUMBER
PL 00142/0335
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
September 1991 / August 1998
10
DATE OF REVISION OF THE TEXT
10/08/2016