1. Name Of The Medicinal Product
VALNI XL 30 mg PROLONGED RELEASE TABLETS
2. Qualitative And Quantitative Composition
Each tablet contains 30 mg of nifedipine
For excipients see 6.1
3. Pharmaceutical Form
Prolonged release tablet
Each pale red tablet is round and biconvex and embossed with "30" on one side.
4. Clinical Particulars
4.1 Therapeutic Indications
The tablets are indicated for:
- the treatment of all grades of hypertension
- the prophylaxis of chronic stable angina pectoris, either as monotherapy or in combination with a beta-blocker
4.2 Posology And Method Of Administration
Route of Administration
For oral use
These tablets should be swallowed whole with a glass of water and not bitten, broken up or chewed.
Dosage Recommendations
It is recommended that each dose should be taken at approximately 24 hours 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 20 mg tablet once daily. In severe hypertension and the prophylaxis of angina pectoris the recommended initial dose is one 30 mg tablet once daily. The dose may be adjusted to a maximum of 90 mg 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 30 mg nifedipine, once daily. Subsequent titration to a higher dosage should be according to clinical response.
Elderly: The pharmacokinetics of nifedipine may be altered in the elderly therefore, a lower maintenance dose may be necessary when treating elderly 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.
Children: Nifedipine is not recommended for use in children.
Treatment with nifedipine may be continued long term.
4.3 Contraindications
VALNI XL 30 mg PROLONGED RELEASE TABLETS are contraindicated:
- in patients with a known hypersensitivity to the drug or other constituents of the tablets
- in patients with a known hypersensitivity to other dihydropyridines calcium antagonists, because of the theoretical risk of cross-reactivity
- in women who are or may become pregnant, are capable of child bearing or to nursing mothers
- in patients with clinically significant aortic stenosis, in cardiogenic shock or unstable angina or for the treatment of acute attacks of angina
- in patients with inflammatory bowel disease, Crohn's disease or with a history of gastrointestinal obstruction, oesophageal obstruction or with decreased diameter of the gastrointestinal lumen
- in patients with hepatic impairment
- for secondary prevention of myocardial infarction or during or within one month of a myocardial infarction
VALNI XL 30 mg PROLONGED RELEASE TABLETS should not be administered concomitantly with rifampicin since effective plasma levels of nifedipine may not be achieved owing to enzyme induction (see section 4.5).
The safety of nifedipine prolonged release tablets has not been established in patients with malignant hypertension.
4.4 Special Warnings And Precautions For Use
Nifedipine should be used with caution in patients with hypotension, as there is a risk of blood pressure decreasing further and in patients whose cardiac reserve is poor. Deterioration of heart failure has occasionally been observed with nifedipine.
Cardiac ischaemic pain has been reported to occur in a small proportion of patients following the introduction of nifedipine therapy. In such cases, treatment with nifedipine should be discontinued.
Caution should be exercised when nifedipine tablets are given to diabetic patients as they may require adjustment of their diabetic therapy.
In patients with malignant hypertension and hypovolaemia and who are on dialysis, a significant decrease in blood pressure can occur.
Nifedipine may be used in combined therapy with other antihypertensive agents including beta-blocker drugs, but the possibility of an additive effect resulting in postural hypotension should be borne in mind. Withdrawal of any previous antihypertensive agents should be gradual, as nifedipine will not prevent any possible rebound effects.
Nifedipine is contra-indicated in pregnancy. However, caution must be exercised when nifedipine with intravenous magnesium sulphate is given to pregnant women.
VALNI XL 30 mg PROLONGED RELEASE TABLETS must not be administered to patients with Kock pouch (ileostomy after proctocolectomy).
A false positive effect may be obtained when carrying out a barium contrast X-ray.
VALNI XL 30 mg PROLONGED RELEASE TABLETS contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance e.g. galactosaemia, the Lapp lactase deficiency or glucose-galactose malabsorption, should be advised not to take these tablets.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Known Interactions
Nifedipine 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 Interactions
Nifedipine 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 Nifedipine
Aspirin, 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.
4.6 Pregnancy And Lactation
Nifedipine is contraindicated in woman capable of child-bearing.
Safe use of nifedipine during human pregnancy has not been established. Animal studies have shown reproductive toxicity (embryotoxic and teratogenic effects) at maternally toxic doses.
Nifedipine may be present in breast milk and therefore, VALNI XL 30 mg PROLONGED RELEASE TABLETS are contraindicated for use in nursing mothers.
In single reports of in vitro fertilisation, calcium antagonists like nifedipine have been associated with biochemical alterations in the head of the spermatozoa that may impair sperm function. Calcium antagonists like nifedipine should be considered as possible causes in those men who are repeatedly unsuccessful in fathering a child by in vitro fertilisation and where no other explanation can be found.
4.7 Effects On Ability To Drive And Use Machines
Reactions to nifedipine may vary in intensity in patients, especially at the onset of therapy, on changing medication or when combined with alcohol. Therefore, the patient should be warned of the possible effects and advised not to drive or operate machinery, if affected.
4.8 Undesirable Effects
Most undesirable effects are due to vasodilatory action of nifedipine and usually regress upon withdrawal of treatment.
Those commonly reported (at an incidence of (> 1 % < 10 %) in clinical studies include headache, palpitations, vasodilatation (especially at the start of therapy), lethargy, constipation, dizziness and oedema particularly peripheral oedema not connected with weight gain or heart failure.
Other side effects associated with nifedipine therapy are named below :
|
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
|
|
|
|
|
Haematological
|
|
|
leucopenia, hyperglycaemia
|
|
|
|
|
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
|
|
|
|
|
|
Respiratory
|
dyspnoea
|
epistaxis
|
|
|
|
|
|
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
|
|
There have also been reports of gynaecomastia in older men on long-term therapy, but this usually regresses when treatment is withdrawn.
Exacerbation of angina pectoris has been observed at the start of treatment with modified-release preparations of dihydropyridines, including nifedipine. Myocardial infarction is also known to occur although it is not possible to distinguish it from the natural course of ischaemic heart disease.
4.9 Overdose
Symptoms
There 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.
Management
In 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 25 g for adults and 10 g 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 10 ml to 20 ml of 10 % calcium gluconate, administered intravenously over a period of 5 to 10 minutes. If ineffective, the therapy can be continued, with ECG monitoring.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Anatomical Therapeutic Chemical (ATC) code: C08C A05
Selective calcium channel blocker (dihydropyridine derivative), with mainly vascular effects
Nifedipine is a dihydropyridine and is a specific and potent antagonist of calcium influx through the slow channel of the cell membrane of cardiac and smooth muscle cells, both in coronary and peripheral circulation.
The antihypertensive effects of nifedipine are achieved by causing peripheral vasodilatation resulting in a reduction in peripheral resistance. Nifedipine administered once daily provides twenty-four hours control of elevated blood pressure. Nifedipine reduces blood pressure such that the percentage lowering is proportional to its initial level. In normotensive individuals, nifedipine has little or no effect.
Nifedipine produces its effects in the treatment of angina by reducing peripheral and coronary vascular resistance, leading to an increase in coronary blood flow, cardiac output and stroke volume and causing a decrease in after-load. Also, nifedipine submaximally dilates clear and atherosclerosis coronary arteries to protect the heart against coronary artery spasm and improve perfusion to the ischaemic myocardium. Nifedipine decreases the frequency of painful attacks and the ischaemic ECG changes regardless of the relative contribution from coronary artery spasm or atheroschlerosis.
5.2 Pharmacokinetic Properties
General Characteristics
VALNI XL 30 mg PROLONGED RELEASE 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 concentrations versus time profile at steady state are plateau-like, rendering the VALNI XL 30 mg PROLONGED RELEASE TABLETS suitable for once daily administration.
Absorption
Nifedipine 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.
Distribution
Nifedipine is about 95 % bound to plasma proteins.
Metabolism
Nifedipine is almost completely metabolised in the liver by oxidative and hydrolytic processes.
Elimination
The 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 Impairment
There 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 Impairment
Nifedipine 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.
5.3 Preclinical Safety Data
The LD50 values (in mg per Kg) determined when nifedipine was given orally and intravenously to different animal species, are reported below:
Animal Species
|
Oral
|
Intravenous
|
|
|
|
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
|
* 95 % confidence interval
Subacute & Subchronic Toxicity Studies (in Rats and Dogs)
Nifedipine doses of up to 50 mg per Kg in rats and 100 mg 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 2.5 mg per Kg in rats and 0.1 mg 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 100 mg 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 100 ppm in the feed (about 5 mg to 7 mg 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 Studies
In vivo and in vitro studies showed that nifedipine has no mutagenic properties.
6. Pharmaceutical Particulars
6.1 List Of Excipients
In Tablet Core
Povidone K30
Lactose monohydrate
Carbomer 974P
Silica, colloidal anhydrous
In Tablet Core & Coat
Talc
Hypromellose (E. 464)
Magnesium stearate
In Tablet Coat
Dimethylaminoethyl methacrylate-Butyl methacrylate-Methyl methacrylate copolymer
Macrogol 4000
Red iron oxide (E. 172)
Titanium dioxide (E. 171)
6.2 Incompatibilities
Not applicable.
6.3 Shelf Life
Shelf Life of the Medicinal Product as Packaged for Sale
36 months
Shelf Life After Dilution or Reconstitution
Not applicable
Shelf Life After First Opening the Container
Not applicable
6.4 Special Precautions For Storage
Do not store above 25 ºC. Keep blister in the outer carton.
6.5 Nature And Contents Of Container
The tablets are enclosed in blisters composed of 25 µm aluminium foil coated with 20 g m-2 PVDC film / 250 µm PVC foil coated with 40 g m-2 PVDC film
The blisters are boxed in cardboard cartons containing 28 tablets and a patient information leaflet.
6.6 Special Precautions For Disposal And Other Handling
No special requirements.
7. Marketing Authorisation Holder
Winthrop Pharmaceuticals UK Limited
One Onslow Street
Guildford
Surrey
GU1 4YS
United Kingdom
trading as: Winthrop Pharmaceuticals, PO Box 611, Guildford, Surrey, GU1 4YS
8. Marketing Authorisation Number(S)
PL 17780/0317
9. Date Of First Authorisation/Renewal Of The Authorisation
22/10/2007
10. Date Of Revision Of The Text
13 May 2008
