For the treatment of all grades of hypertension.

 

For the prophylaxis of chronic stable angina pectoris either as monotherapy or in combination with a beta-blocker.

Posology

         

          In mild to moderate hypertension, the recommended initial dose is one 20 mg tablet once-daily. In severe hypertension, the recommended initial dose is one 30 mg tablet once-daily.  If necessary, the dosage can be increased according to individual requirements up to a maximum of 90 mg once-daily.

 

          For the prophylaxis of angina pectoris, the recommended initial dose is one 30 mg tablet once-daily. The dosage can be increased according to individual requirements up to a maximum of 90 mg once-daily.

 

          Patients in whom hypertension or anginal symptoms are controlled on Adalat capsules or Adalat retard may be safely switched to Adalat LA. Prophylactic anti-anginal efficacy is maintained when patients are switched from other calcium antagonists such as diltiazem or verapamil to Adalat LA. Patients switched from other calcium antagonists should initiate therapy at the recommended initial dose of 30 mg Adalat LA once-daily. Subsequent titration to a higher dose may be initiated as warranted clinically.

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 treatment

 

          Treatment may be continued indefinitely.

  

          Additional information on special populations

 

Paediatric population

The safety and efficacy of Adalat LA in children below 18 years has not been established. Currently available data for the use of nifedipine in hypertension are described in section 5.1

 

Elderly

Based on pharmacokinetic data for Adalat LA no dose adaptation in elderly people above 65 years is necessary.

 

          Renal impairment

Based on pharmacokinetic data, no dosage adjustment is required in patients with renal impairment (see section 5.2).

 

          Method of administration

 

          Oral use.

 

The tablets should be swallowed whole with a glass of water, either with or without food.  The tablets should be taken at approximately 24-hour intervals, i.e. at the same time each day, preferably during the morning. Adalat LA tablets must be swallowed whole; under no circumstances should they be bitten, chewed or broken up.

 

          Adalat LA should not be taken with grapefruit juice (see section 4.5).

Adalat LA should not be administered to patients with known hypersensitivity to the active substance, or to other dihydropyridines because of the theoretical risk of cross-reactivity, or to any of the excipients listed in section 4.4 and 6.1. Adalat LA should not be used in cases of cardiogenic shock, clinically significant aortic stenosis, unstable angina, or during or within one month of a myocardial infarction. Adalat LA should not be used for the treatment of acute attacks of angina. The safety of Adalat LA in malignant hypertension has not been established. Adalat LA should not be used for secondary prevention of myocardial infarction. Owing to the duration of action of the formulation, Adalat LA should not be administered to patients with hepatic impairment. Adalat LA should not be administered to patients with a history of gastro-intestinal obstruction, oesophageal obstruction, or any degree of decreased lumen diameter of the gastro-intestinal tract. Adalat LA must not be used in patients with a Kock pouch (ileostomy after proctocolectomy). Adalat LA is contra-indicated in patients with inflammatory bowel disease or Crohn's disease. Adalat LA 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).

          Adalat LA tablets must be swallowed whole; under no circumstances should they be bitten, chewed or broken up.

 

          Caution should be exercised in patients with hypotension as there is a risk of further reduction in blood pressure and care must be exercised in patients with very low blood pressure (severe hypotension with systolic blood pressure less than 90 mm Hg).

 

          Adalat LA should not be used during pregnancy unless the clinical condition of the woman requires treatment with nifedipine. Adalat LA should be reserved for women with severe hypertension who are unresponsive to standard therapy (see section 4.6).

 

          Careful monitoring of blood pressure must be exercised when administering nifedipine with I.V. magnesium sulfate, owing to the possibility of an excessive fall in blood pressure, which could harm both mother and foetus. For further information regarding use in pregnancy, refer to section 4.6.

 

          Adalat LA is not recommended for use during breast-feeding because nifedipine has been reported to be excreted in human milk and the effects of nifedipine exposure to the infant are not known (see section 4.6).

 

In patients with impaired liver function careful monitoring and, in severe cases, a dose reduction may be necessary.

 

          Adalat LA may be used in combination with beta-blocking drugs and other antihypertensive agents but the possibility of an additive effect resulting in postural hypotension should be borne in mind.  Adalat LA will not prevent possible rebound effects after cessation of other antihypertensive therapy.

 

          Adalat LA should be used with caution in patients whose cardiac reserve is poor. Deterioration of heart failure has occasionally been observed with nifedipine.

 

                      Diabetic patients taking Adalat LA may require adjustment of their control.

 

          In dialysis patients with malignant hypertension and hypovolaemia, a marked decrease in blood pressure can occur.

 

          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 known inhibitors of the cytochrome P450 3A4 system, and which may therefore lead to increased plasma concentrations of nifedipine include, for example:

 

          -         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.

 

          As the outer membrane of the Adalat LA tablet is not digested, what appears to be the complete tablet may be seen in the toilet or associated with the patient’s stools. Also, as a result of this, care should be exercised when administering Adalat LA to patients, as obstructive symptoms may occur. Bezoars can occur in very rare cases and may require surgical intervention.

 

          In single cases, obstructive symptoms have been described without known history of gastrointestinal disorders.

 

          A false positive effect may be experienced when performing a barium contrast x-ray.

 

          For use in special populations see section 4.2.

 

          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 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 drugs

 

          Nifedipine may increase the blood pressure lowering effect of concomitant applied antihypertensives.

 

          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.

 

          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.

 

         

Antiarrhythmics

          Flecainide: There has been too little experience with the coadministration of Tambocor with nifedipine to recommend concomitant use.

 

          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.

 

          Calcium Channel Blockers

Verapamil: Verapamil, a CYP3A inhibitor, can inhibit the metabolism of nifedipine and increase the exposure to nifedipine during concomitant therapy. Blood pressure should be monitored and reduction of the dose of nifedipine considered.

 

Angiotensin-II Blockers

Irbesartan: In vitro studies show significant inhibition of the formation of oxidized irbesartan metabolites by nifedipine. However, in clinical studies, concomitant nifedipine had no effect on irbesartan pharmacokinetics.

Candesartan: No significant drug interaction has been reported in studies with candesartan cilexitil given together with nifedipine.

Because candesartan is not significantly metabolized by the cytochrome P450 system and at therapeutic concentrations has no effect on cytochrome P450 enzymes, interactions with drugs that inhibit or are metabolized by those enzymes would not be expected.

 

Beta-blockers

Adalat CC was well tolerated when administered in combination with beta-blockers in 187 hypertensive patients in a placebo-controlled clinical trial. However, there have been occasional literature reports suggesting that the combination nifedipine and beta-adrenergic blocking drugs may increase the likelihood of congestive heart failure, severe hypotension or exacerbation of angina in patients with cardiovascular disease. Clinical monitoring is recommended and a dose adjustment of nifedipine should be considered.

Timolol: Hypotension is more likely to occur if dihydropryridine calcium antagonists such as nifedipine are co-administered with timolol.

 

Central Alpha1-Blockers

Doxazosin: Healthy volunteers participating in a multiple dose doxazosin-nifedipine interaction study received 2 mg doxazosin q.d. alone or combined with 20 mg nifedipine ER b.i.d. Co-administration of nifedipine resulted in a decrease in AUC and Cmax of doxazosin to 83% and 86% of the values in the absence of nifedipine, respectively.

In the presence of doxazosin, AUC and Cmax of nifedipine were increased by factors of 1.13 and 1.23, respectively. Compared to nifedipine monotherapy, blood pressure was lower in the presence of doxazosin. Blood pressure should be monitored when doxazosin is coadministered with nifedipine, and dose reduction of nifedipine considered.

 

Antithrombotics

Coumarins: There have been rare reports of increased prothrombin time in patients taking coumarin anticoagulants to whom nifedipine was administered. However the relationship to nifedipine therapy is uncertain.

 

Platelet Aggregation Inhibitors

Clopidogrel: No clinically significant pharmacodynamic interactions were observed when clopidrogrel was co-administered with nifedipine. Tirofiban: Co-administration of nifedipine did not alter the exposure to tirofiban importantly.

 

Other

Diuretics, PDE5 inhibitors, alpha-methyldopa: Nifedipine may increase the blood pressure lowering effect of these concomitantly administered agents.

 

Antisecretory Drugs

Omeprazole: In healthy volunteers receiving a single dose of 10 mg nifedipine, AUC and Cmax of nifedipine after pretreatment with omeprazole 20 mg q.d. for 8 days were 1.26 and 0.87 times those after pre-treatment with placebo. Pretreatment with or co-administration of omeprazole did not impact the effect of nifedipine on blood pressure or heart rate. The impact of omeprazole on nifedipine is not likely to be of clinical relevance.

Pantoprazole: In healthy volunteers the exposure to neither drug was changed significantly in the presence of the other drug.

Ranitidine: Five studies in healthy volunteers investigated the impact of multiple ranitidine doses on the single or multiple dose pharmacokinetics of nifedipine. Two studies investigated the impact of co-administered ranitidine on blood pressure in hypertensive subjects on nifedipine. Coadministration of ranitidine did not have relevant effects on the exposure to nifedipine that affected the blood pressure or heart rate in normotensive or hypertensive subjects. Cisapride: Simultaneous administration of cisapride and nifedipine may lead to increased plasma concentrations of nifedipine.

Sirolimus: A single 60 mg dose of nifedipine and a single 10 mg dose of sirolimus oral solution were administered to 24 healthy volunteers.

Clinically significant pharmacokinetic drug interactions were not observed.

 

Glucose Lowering Drugs

Pioglitazone: Co-administration of pioglitazone for 7 days with 30 mg nifedipine ER administered orally q.d. for 4 days to male and female volunteers resulted in least square mean (90% CI) values for unchanged nifedipine of 0.83 (0.73-0.95) for Cmax and 0.88 (0.80-0.96) for AUC relative to nifedipine monotherapy. In view of the high variability of nifedipine pharmacokinetics, the clinical significance of this finding is unknown.

Rosiglitazone: Co-administration of rosiglitazone (4 mg b.i.d.) was shown to have no clinically relevant effect on the pharmacokinetics of nifedipine.

Metformin: A single dose metformin-nifedipine interaction study in normal healthy volunteers demonstrated that co-administration of nifedipine increased plasma metformin Cmax and AUC by 20% and 9%, respectively, and increased the amount of metformin excreted in urine. Tmax and half-life were unaffected. Nifedipine appears to enhance the absorption of metformin.

Miglitol: No effect of miglitol was observed on the pharmacokinetics and pharmacodynamics of nifedipine. Repaglinide: Co-administration of 10 mg nifedipine with a single dose of 2 mg repaglinide (after 4 days nifedipine 10 mg t.i.d. and repaglinide 2 mg t.i.d.) resulted in unchanged AUC and Cmax values for both drugs.

 

Acarbose: Nifedipine tends to produce hyperglycemia and may lead to loss of glucose control. If nifedipine is co-administered with acarbose, blood glucose levels should be monitored carefully and a dose adjustment of nifedipine considered.

Drugs Interfering with Food Absorption Orlistat: In 17 normal-weight subjects receiving orlistat 120 mg t.i.d. for 6 days, orlistat did not alter the bioavailability of 60 mg nifedipine (extended release tablets).

 

Herbals

St. John’s Wort: St. John’s Wort is an inducer of CYP3A and may decrease exposure to nifedipine. Alternative antihypertensive therapy should be considered in patients in whom St. John’s Wort therapy is necessary.

 

          Drug food interactions

 

          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 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 interaction

 

          Nifedipine may increase the spectrophotometric values of urinary vanillylmandelic acid, falsely.  However, HPLC measurements are unaffected.

 

                      Pregnancy

                     

                      Nifedipine 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 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-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 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).

 

          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.

         

Reactions to the drug, which vary in intensity from individual to individual, may 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.

Adverse 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 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		Nosebleed Nasal congestion		Dyspnoea Pulmonary  oedema**
Gastrointestinal Disorders	Constipation	Gastrointestinal and abdominal pain Nausea Dyspepsia Flatulence Dry mouth	Gingival hyperplasia	Bezoar Dysphagia Intestinal obstruction Intestinal ulcer 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

 

* = 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.

          To report any side effect(s):

National Pharmacovigilance and Drug Safety Center (NPC).

Fax: + 966 - 11 - 205 - 7662.

Call NPC at +966 - 11 - 2038222,

Ext.: 2317 - 2356 - 2353 - 2354 - 2334 - 2340.

Toll - free: 8002490000.

E - mail: npc.drug@sfda.gov.sa.

Website: www.sfda.gov.sa/npc

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, tachycardia, bradycardia, hyperglycaemia, metabolic acidosis, hypoxia, cardiogenic shock with pulmonary oedema.

 

          Treatment

          As 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 sulphate).

 

          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.

                      Pharmacotherapeutic group: selective calcium channel blockers with mainly vascular effect, dihydropyridine derivatives, ATC code: C08CA05

         

          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 is to relax arterial smooth muscle, both in the coronary and peripheral circulation.  The Adalat LA tablet is formulated to achieve controlled delivery of nifedipine in a release profile sufficient to enable once-daily administration to be effective in clinical use.

 

          In hypertension, the main action of nifedipine is to cause peripheral vasodilatation and thus reduce peripheral resistance.  Nifedipine administered once-daily provides 24-hour control of raised blood pressure.  Nifedipine causes reduction in blood pressure such that the percentage lowering is proportional to its initial level.  In normotensive individuals, nifedipine has little or no effect on blood pressure.

 

          In angina, Adalat LA 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.

 

          In a multi-national, randomised, double-blind, prospective study involving 6321 hypertensive patients with at least one additional risk factor followed over 3 to 4.8 years, Adalat LA 30 and 60 (nifedipine GITS) were shown to reduce blood pressure to a comparable degree as a standard diuretic combination.

 

          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. Pediatric dosing forms are lacking.

 

General characteristics:

                     

          Adalat LA tablets are formulated to provide nifedipine at an approximately constant rate over 24 hours. Nifedipine is released from the tablet at a zero-order rate by a membrane-controlled, osmotic push-pull process. The pharmacokinetic profile of this formulation is characterized by low peak-trough fluctuation. 0-24 hour plasma concentration versus time profiles at steady state are plateau-like, rendering the Adalat LA tablet appropriate for once-a-day administration.

 

          The delivery rate is independent of gastrointestinal pH or motility. Upon swallowing, the biologically inert components of the tablet remain intact during gastrointestinal transit and are eliminated in the faeces as an insoluble shell.

 

          Absorption

          Orally administered nifedipine is almost completely absorbed in the gastro-intestinal tract.  The systemic availability of orally administered nifedipine immediate release formulations (nifedipine capsules) is 45–56% owing to a first pass effect.   At steady-state, the bioavailability of Adalat LA tablets ranges from 68-86% relative to Adalat capsules.  Administration in the presence of food slightly alters the early rate of absorption but does not influence the extent of drug availability.

 

          Distribution

          Nifedipine is about 95% bound to plasma protein (albumin). The distribution half-life after intravenous administration has been determined to be 5 to 6 minutes.

 

          Biotransformation

          After 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 eliminated in the form of its metabolites, predominantly via the kidneys, with approximately 5-15% being excreted via the bile in the faeces.  Non-metabolised nifedipine can be detected only in traces (below 0.1%) in the urine. 

           

                      Elimination

          The terminal elimination half-life is 1.7 to 3.4 h in conventional formulations (nifedipine capsules). The terminal half-life following Adalat LA administration does not represent a meaningful parameter as a plateau-like plasma concentration is maintained during release from the tablets and absorption. After release and absorption of the last dose the plasma concentration finally declines with an elimination half-life as seen in conventional formulations.

 

          Characteristics in patients:

 

       There are no significant differences in the pharmacokinetics of nifedipine between healthy subjects and subjects with renal impairment. Therefore, dosage adjustment is not needed in these patients.

 

       In patients with hepatic impairment, the elimination half-life is distinctly prolonged and the total clearance is reduced.  Owing to the duration of action of the formulation, Adalat LA should not be administered in these patients.

Preclinical data reveal no special hazards for humans based on conventional studies of single and repeated dose toxicity, genotoxicity and carcinogenic potential.

 

          Following acute oral and intravenous administration of nifedipine in various animal species, the following LD₅₀ (mg/kg) values were obtained:

 

Mouse:	Oral: 494 (421-572)*;	i.v.:  4.2 (3.8-4.6)*.
Rat:	Oral:  1022 (950-1087)*;	i.v.:  15.5 (13.7-17.5)*.
Rabbit	Oral:  250-500;	i.v.:  2-3.
Cat:	Oral:  ~ 100;	i.v.:  0.5-8.
Dog:	Oral:   > 250;	i.v.:  2-3.
* 95% confidence interval.

 

 

          In subacute and subchronic toxicity studies in rats and dogs, nifedipine was tolerated without damage at doses of up to 50 mg/kg (rats) and 100 mg/kg (dogs) p.o. over periods of thirteen and four weeks, respectively.  Following intravenous administration, dogs tolerated up to 0.1 mg/kg nifedipine for six days without damage.  Rats tolerated daily intravenous administration of 2.5 mg/kg nifedipine over a period of three weeks without damage.

           

          In chronic toxicity studies in dogs with treatment lasting up to one year, nifedipine was tolerated without damage at doses up to and including 100 mg/kg p.o.  In rats, toxic effects occurred at concentrations above 100 ppm in the feed (approximately 5-7 mg/kg bodyweight).

 

          In a carcinogenicity study in rats (two years), there was no evidence of a carcinogenic effect of nifedipine.

 

          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.

 

          In in vitro and in vivo tests, nifedipine has not been associated with mutagenic properties.

          Tablet Core

          Polyethylene oxide

          Hypromellose (5 cp)

          Magnesium stearate

          Sodium chloride

          Ferric oxide, red (E172)

         

          Coating

          Cellulose acetate

          Macrogol (3350)

          Hydroxypropylcellulose

          Hypromellose (3 cp)

          Propylene glycol

          Hypromellose (5 cp)

          Titanium dioxide (E171)

          Ferric oxide, red (E172)

 

          Polish and Print

          Black ink for printing Opacode S-1-17823

          (Contains: iron oxide black (E172) and Shellac)

 

          Not applicable.

PP blister packs: 4 years

Store in the original container. The tablets should be protected from strong light. Do not store above 25°C

Blister strips composed of polyamide/aluminium/polyvinyl chrloride / aluminium foil - in folding boxes, containing 30 tablets

          No additional information