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Adalat

Bayer Healthcare Pharmaceuticals Inc.
Website: http://pharma.bayer.com

Brand Name

Adalat

Manufacturer

Bayer Pharma AG 51368 Leverkusen, Germany

Therapeutic Class

Calcium channel blockers (CCBs)

Dosage Form, Composition & NAFDAC Registration Number (NRN)

Tablet (NRN: ): Each prolonged-release tablet contains 30 mg nifedipine. For a full list of excipients see "List of excipients"

Pack Size: Alu/Alu-blister: 3 x 10 Tablets

Adalat LA 30

Tablet (NRN: ): Each prolonged-release tablet contains 60 mg nifedipine. For a full list of excipients see "List of excipients"

Pack Size: Alu/Alu-blister: 3 x 10 Tablets

Adalat LA 60

Pharmacology

Pharmacodynamic Properties

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.

Nifedipine acts particularly on the cells of the myocardium and the smooth muscle cells of the coronary arteries and the peripheral resistance vessels.

Pharmacokinetic Properties

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

Indications

  • Treatment of coronary heart disease; Chronic stable angina pectoris (angina of effort)
  • Treatment of hypertension
  • Treatment of 6321 hypertensive patients with at least one additional risk factor followed over 3 to 4.8 years in a multi-national, randomised, double-blind, prospective study.
  • Nifedipine (Adalat LA) was shown to reduce cardiovascular and cerebrovascular events to a comparable degree as a standard diuretic combination (see "Pharmacodynamic properties').

Contra-indications

  • Adalat LA must not be used in cases of known hypersensitivity to nifedipine or to any of the excipients (see "List of excipients').
  • Nifedipine is contraindicated in pregnancy before week 20 and during breastfeeding (see "Pregnancy and lactation’’).
  • Adalat LA must not be used in cases of cardiovascular shock.
  • Adalat LA must not be used in patients with Kock pouch (ileostomy after proctocolectomy).
  • Nifedipine must not be used in combination with rifampicin because no efficient plasma levels of nifedipine may be obtained due to enzyme induction (see "Interaction with other medicinal products and other forms of interactions';

Precautions/Warnings

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.

There are no safety and efficacy data from well-controlled studies in pregnant women. Animal studies have shown a variety of embryotoxic, placentotoxic and fetotoxic effects (see "Preclinical safety data') when administered during and after the period of organogenesis.

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 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.

Careful monitoring of blood pressure must be exercised, also when administered nifedipine with i.v. magnesium sulfate, owing to the possibility of an excessive fall in blood pressure which could harm both mother and fetus. As with other non-deformable material (see "Instructions for use/ handling').

Care should be used when administering Adalat LA in patients with pre-existing severe gastrointestinal narrowing because 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.

When doing barium contrast X-ray Adalat LA may cause false positive effects (e.g. filling defects interpreted as polyp).
In patients with impaired liver function careful monitoring and, in severe cases, a dose reduction may be necessary (see "Pharmacokinetic properties').

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 "Interaction with other medicinal products and other forms of interaction').

Drugs, which are inhibitors of the cytochrom 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 "Dosage and method of administration’'.

Interactions

 

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 "Special warnings and precautions for use"). 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 contra-indicated (see "Contraindications').

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 "Dosage and method of administration').

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 "Special warnings and precautions for use'). 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 "Special warnings and precautions for use").

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 "Special warnings and precautions for use').

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 co-administration of both drugs cannot be excluded (see "Special warnings and precautions for use').

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 co-administration of both drugs cannot be excluded (see "Special warnings and precautions for use").

Quinupristin/Dalfopristin

Simultaneous administration of quinupristin I dalfopristin and nifedipine may lead to increased plasma concentrations of nifedipine (see "Special warnings and precautions for use';.

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 "Special warnings and precautions for use').

Cimetidine

Due to its inhibition of cytochrome P450 3A4, cimetidine elevates the plasma concentrations of nifedipine and may potentiate the antihypertensive effect (see "Special warnings and precautions for use').

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,
- β-blockers,
- ACE-inhibitors,
- Angiotensin 1 (AT1) receptor- antagonists,
- other calcium antagonists,
- α-adrenergic blocking agents,
- PDE5 inhibitors,
- α-methyldopa.
When nifedipine is administered simultaneously with 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 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 have 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 coadministration 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 3 days after the last ingestion of grape-fruit juice. Ingestion of grapefruit/grapefruit juice is therefore to be avoided while taking nifedipine (see "Dosage and method of administration';.

Other forms of interaction:
Nifedipine may cause falsely increased spectrophotometric values of urinary vanillyl-mandelic acid. However, measurement with HPLC is unaffected.

Pregnancy and lactation

Pregnancy
Nifedipine is contraindicated in pregnancy before week 20 (see "Contraindications");. There are no adequate and well controlled studies in pregnant women. In animal studies nifedipine has been shown to produce embryotoxicity, fetotoxicity and teratogenicity (see "Preclinical safety data').

Lactation
Nifedipine passes into the breast milk. As there is no experience of possible effects on infants, breastfeeding should first be stopped if nifedipine treatment becomes necessary during the breastfeeding period.

In-vitro fertilization

In 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.

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 "Undesirable effects'). This applies particularly at the start of the treatment, on changing the medication and in combination with alcohol.

Adverse Effects

Adverse drug reactions (ADRs) based on placebo-controlled studies with nifedipine sorted by CIOMS Ill 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 post marketing 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
1)
 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
Vasodilatation 
Hypotension Syncope    
Respiratory, thoracic, and mediastinal disorders   Nosebleed
Nasal congestion
 

Dyspnea 

Gastrointestinal disorders Constipation 

Groinasttestinal and abdominal pain

Nausea
Dyspepsia
Flatulence
Dry mouth

Gingival hyperplasia 

Bez oar
Dysphagia
Intestinal obstruction
Intestinal ulcer
Vomiting
Gastro oesophageal 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
   

1= may result in life-threatening outcome.
In dialysis patients with malignant hypertension and hypovolaemia a distinct fall in blood pressure can occur as a result of vasodilation.

Dosage & Administration

Method of administration
Oral use

Dosage regimen:
As far as possible the treatment must be tailored to the needs of the individual. Depending on the clinical picture in each case, the basic dose must be introduced gradually.

Unless otherwise prescribed, the following dosage guidelines are recommended for adults:

For coronary heart disease:

Chronic stable angina pectoris (angina of effort)
1 Adalat LA 30 mg tablet once daily (1 x 30 mg/day)
1 Adalat LA 60 mg tablet once daily (1 x 60 mg/day)

For hypertension:
1 Adalat LA 30 mg tablet once daily (1 x 30 mg/day)
1 Adalat LA 60 mg tablet once daily (1 x 60 mg/day)

In general, therapy should be initiated with 30 mg once daily. Where registered a starting dose of 20 mg once daily may be considered when medically indicated. Depending on the severity of the disease and the patient's response the dose can be increased in stages up to 120 mg once daily.

Coadministration 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 "Interaction with other medicinal products other forms of interaction").

Duration of Treatment
The attending doctor will determine the duration of use.

ADMINISTRATION

As a rule Adalat LA tablets are swallowed whole with a little liquid, irrespective of meal times. Grapefruit juice is to be avoided (see "Interaction with other medicinal products and other forms of interaction).

ADDITIONAL INFORMATION ON SPECIAL POPULATIONS

Children and adolescents
The safety and efficacy of Adalat LA in children below 18 years has not been established.

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

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

Patients with renal impairment
Based on pharmacokinetic data no dosage adjustment is required in patients with renal impairment (see ''pharmacokinetic’’). The tablets must not be chewed or broken up.

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 the active substance 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.

Particularly in cases of intoxication with slow-release products like Adalat LA elimination must be as complete as possible, including the small intestine, to prevent the otherwise inevitable 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).

Bradycardiac heart rhythm disturbances may be treated symptomatically with 13-sympathomimetics, and in life-threatening bradycardiac disturbances of heart rhythm temporary pacemaker therapy can be advisable. Hypotension as a result of cardiogenic shock and arterial vasodilation 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, vaso-constricting sympathomimetics such as dopamine or noradrenaline are additionally administered. The dosage of these drugs is determined solely by the effect obtained. Additional liquid or volume must be administered with caution because of the danger of overloading the heart.

Storage/Handling Recommendations

In Adalat LA the medication is contained within a non-absorbable shell that slowly releases the drug for the body to absorb. When this process is completed, the empty tablet is eliminated from the body and may be noticed in the stool.

The light-sensitive active substance contained in Adalat LA is protected from light inside and outside its packaging. The tablets must be protected from humidity and must therefore only be removed from the foil immediately before use.

Do not store above 30oC.

Keep out of reach of children.

Review Date

2017-02-15 07:17:54