INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION

Logo ADALAT® 5 mg, 10 mg [DISCONTINUED IN RSA]

SCHEDULING STATUS:
S3

PROPRIETARY NAME
(and dosage form):

ADALAT® 5 mg, 10 mg [DISCONTINUED IN RSA]
Capsules

COMPOSITION:
Each capsule contains 5 mg or 10 mg
nifedipine.

PHARMACOLOGICAL CLASSIFICATION:
A 7.1. Vasodilators, hypotensives.

PHARMACOLOGICAL ACTION:
Nifedipine, a calcium antagonist, improves oxygen supply to the myocardium with simultaneous decrease of oxygen requirements. Nifedipine has a vasodilatory effect on the peripheral arterial beds causing a fall in peripheral vascular resistance and an increase in peripheral blood flow. Ca2+-channel blockers are useful in low-renin hypertension. Nifedipine dilates submaximally both clear and atherosclerotic coronary arteries, thus protecting the heart against coronary artery spasm and improving perfusion to the ischaemic myocardium.

INDICATIONS:
Treatment and prophylaxis of chronic stable angina pectoris, including Prinzmetal's angina. Intermittent arterial vasospasm (Raynaud's) in the absence of any underlying collagen, arteriosclerotic or other vascular disease. Initial management of hypertensive emergency.

CONTRA-INDICATIONS:
ADALAT may not be used at any time during pregnancy and lactation or in cases of hypersensitivity to nifedipine. ADALAT must not be used in cardiovascular shock. ADALAT must not be used in unstable angina and during or within one month of a myocardial infarction. 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.
In single cases of in-vitro fertilization, nifedipine has been associated with reversible biochemical changes in the spermatozoa's head section that may result in impaired sperm function. In men who are repeatedly unsuccessful in fathering a child by in-vitro fertilization and if no other explanation can be found, nifedipine should be considered a possible reason.
Nifedipine is contra-indicated in combination with rifampicin since effective plasma levels of nifedipine may not be achieved owing to enzyme induction by rifampicin.

WARNINGS:
There is some concern about increased mortality and morbidity in the treatment of ischaemic heart disease at dosages higher than those recommended.
Angina pectoris may occur with immediate release nifedipine, especially at the start of the treatment or at the time of dosage increase. The occurrence of myocardial infarction has also been described.
There is no evidence that immediate release nifedipine confers benefit in secondary prevention of myocardial infarction.
Treatment with immediate release nifedipine may induce an exaggerated fall in blood pressure with reflex tachycardia, which could result in cardiovascular complications such as myocardial and cerebrovascular ischaemia.

DOSAGE AND DIRECTIONS FOR USE:
The usual dose is 10 mg to 20 mg three times daily. It is recommended that the dose does not exceed 60 mg daily. In the event of more frequent doses being prescribed, patients should allow an interval of at least two hours between doses.
For optimal adjustment of dosage, where a reduction of possible side effects or greater flexibility of dosage is desired, use of the 5 mg capsule is recommended (at a dosage of 5 mg - 20 mg three times a day). Usually the capsules should be swallowed whole with some fluid before meals.
Threat of angina pectoris attack:
As a more rapid onset of action is required for impending attacks of angina pectoris, the capsule should be bitten through and swallowed immediately with the contents.
Treatment of hypertensive emergency:
5 mg-10 mg orally.
If the effect is insufficient, depending on the reaction of the blood pressure, a further 5 mg or 10 mg dose can be administered after at least 30 min. If the dosage intervals are shorter and/or the dose higher, dangerous hypotensive states can occur.
The recommended dosage regimen for the treatment of intermittent arteriolar vasospasm (Raynaud's) is 10 mg to 20 mg three times daily, according to the response. Should a decision be made to discontinue ADALAT, this should be done gradually, particularly when high doses are used.

SIDE EFFECTS AND SPECIAL PRECAUTIONS:
The following side-effects have been observed:
Incidence of frequency >1% <10%
Body as whole: headache
Cardiovascular system: peripheral edema, vasodilatation
Digestive system: nausea
Nervous system: dizziness
Incidence of frequency >0,1% <1%
Body as whole: Abdominal pain, asthenia, chest pain, edema, and malaise
Cardiovascular system: Angina pectoris, hypotension, palpitation, postural hypotension, and tachycardia
Digestive system: Constipation, diarrhoea, dry mouth, dyspepsia, gastrointestinal disorder
Nervous system: Agitation, nervousness, sleep disorder tremor, vertigo
Respiratory system: Dyspnea
Skin and appendages: Pruritus, rash, sweating
Special senses: Abnormal vision
Incidence of frequency >0,01% <0,1%
Body as a whole: Abdomen enlarged, allergic reaction, and pain
Cardiovascular system: Syncope
Digestive system: Anorexia, flatulence, vomiting
Metabolic and nutritional
disorder:
Hyperglycemia
Musculo-skeletal
system:
Myalgia
Nervous system: Hypesthesia, insomnia, paresthesia, and somnolence
Skin and appendages: Skin disorder
Urogenital system: Polyuria
Others
Incidence of frequency <0,01%
Cardiovascular system: Hypotension which may lead to prolonged QT interval and ventricular fibrillation
Digestive system: Gum hyperplasia, abnormal liver function test
Haemic and lymphatic
system:
Agranulocytosis, purpura
Metabolic and nutritional
disorder:
Hyperglycemia
Skin and appendages: Exfoliative dermatitis, gynaecomastia, photosensitive dermatitis, and urticaria
Although a "steal" effect has not been demonstrated, patients experiencing this effect should discontinue nifedipine therapy.

Special Precautions:
Care should be exercised in dialysis patients with malignant hypertension and irreversible kidney failure with hypovolaemia as a marked fall in blood pressure may occur.
Caution should be exercised in angina patients with hypotension.
A transient increase in blood glucose has been noted. Care must be taken in patients with diabetes mellitus.
ADALAT should be used with caution in patients with a poor cardiac reserve.
In patients with impaired liver function, careful monitoring of the dosage is recommended and in severe cases, a dose reduction may be necessary.
There are no recommendations for use in children.
ADALAT does not replace the nitroglycerines in an acute attack of angina pectoris.
Effect 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 operate machinery. This applies particularly at the start of the treatment, on changing the medication and in combination with alcohol.
Drug Interactions:
- The blood-pressure lowering effect of nifedipine may be potentiated upon co-administration of other antihypertensive drugs.
-        When nifedipine is administered simultaneously with beta-receptor blockers the patient should be carefully monitored, since fairly severe hypotension can occur. Deterioration of heart failure is also known to develop in isolated cases.
-        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.
-        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.
-        Phenytoin
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.
-        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 is 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.
-        Quinupristin/Dalfopristin
Simultaneous administration of quinupristin/dalfopristin and nifedipine may lead to increased plasma concentrations of nifedipine. Upon co-administration of both drugs, the blood pressure should be monitored and, if necessary, a reduction of the nifedipine dose considered.
-        Cimetidine
Due to its inhibition of cytochrome P450 3A4, cimetidine elevates the plasma concentrations of nifedipine and may potentiate the antihypertensive effect.
-        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 contra-indicated.
-        Diltiazem
Diltiazem decreases the clearance of nifedipine. Nifedipine increases the bioavailability and decreases the clearance of diltiazem. The combination of both drugs should be administered with caution and a reduction of both doses may be considered.
-        Grapefruit Juice
Grapefruit juice inhibits the metabolism of nifedipine. Administration of nifedipine together with grapefruit juice thus results in elevated plasma concentrations of nifedipine due to an increase of drug bioavailability. As a consequence, the blood pressure lowering effect may be increased.
-        Cisapride
Simultaneous administration of cisapride and nifedipine may lead to increased plasma concentrations of nifedipine. Upon co-administration of both drugs, the blood pressure should be monitored and, if necessary, a reduction of the nifedipine dose considered.
Theoretical potential interactions
-        Erythromycin As both nifedipine and erythromycin are metabolised via the cytochrome P450 3A4 system, the potential for a drug interaction cannot be ruled out. Erythromycin is 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.
-        Fluoxetine
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. When fluoxetine is given together with nifedipine, the blood pressure should be monitored and, if necessary, a reduction in the nifedipine dose considered.
-        Indinavir, Ritonavir, Saquinavir
Drugs of this class are known to inhibit the cytochrome P450 3A4 system. In addition, indinavir and ritonavir 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 an increased absorption and decreased elimination cannot be excluded. Upon co-administration, the blood pressure should be monitored and, if necessary, a reduction in the nifedipine dose considered.
-        Ketoconazole, Itraconazole, Fluconazole
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 an increased absorption cannot be excluded. Upon co-administration, the blood pressure should be monitored and, if necessary, a reduction in the nifedipine dose considered.
-        Tacrolimus
Tacrolimus has been shown to be metabolised via the cytochrome P450 3A4 system. Upon co-administration of tacrolimus and nifedipine, the tacrolimus plasma concentrations should be monitored and, if necessary, a reduction in the tacrolimus dose considered.
-        Carbamazepine
As carbamazepine has 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.
-        Phenobarbitone
As phenobarbitone has 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.
-        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.
Interactions shown not to exist
•        Concomitant administration of nifedipine and pantoprazole does not significantly affect the pharmacokinetics of nifedipine.
•        Ranitidine co-administered with nifedipine does not significantly influence the pharmacokinetics of nifedipine.
Other forms of Interactions
Nifedipine may cause falsely increased spectrophotometric values of urinary vanillyl-mandelic acid. However, measurement with HPLC is unaffected.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
Flushing, headaches, lowering of blood pressure, tachycardia or bradycardia, hyperglycaemia, metabolic acidosis, hypoxia, cardiogenic shock with pulmonary oedema, disturbances of consciousness to the point of coma. If these symptoms are observed in time, the first therapeutic measure to be considered is gastric lavage with added medicinal charcoal if necessary in combination with irrigation of the small intestine. Haemodialysis serves no purpose, as nifedipine is not dialysable, but plasmapheresis is advisable. No specific antidote is available.
Treatment is symptomatic and supportive. 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.
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, vasoconstricting sympathomimetics such as dopamine or noradrenaline can additionally be 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.

IDENTIFICATION:
Orange coloured soft gelatine capsules filled with a yellow viscous liquid.

PRESENTATION:
Bottles of 100 capsules of 5 mg nifedipine. Bottles of 100 and 250 capsules of 10 mg nifedipine.

STORAGE INSTRUCTIONS:
Store below 25°C as the gelatine capsules may stick together. Protect from light.
Keep out of reach of children.
PLEASE NOTE:
ADALAT capsules should only be removed from the glass bottle by the patient immediately before use and the cap should be replaced.

REGISTRATION NO:
5 mg:         R/7.1.4/31
10 mg:         G/7.1.4/192
ZIMBABWE PP(10)77/12.1/926

NAME AND BUSINESS ADDRESS OF THE APPLICANT:
Bayer (Pty) Ltd
Wrench Road Isando 1600
Reg. No. 1968/11192/07

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
5 June 2001

® = Registered Trade Mark of Bayer AG, Germany.

Adalatcaps CCDS/SPC/18/SA1        C9003/0601

Letter dated 06 April 2006
Source: Pharmaceutical Industry

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