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

Logo ADALAT® XL 30
ADALAT® XL 60

SCHEDULING STATUS:
S3

PROPRIETARY NAME
(and dosage form):

ADALAT® XL 30
ADALAT
® XL 60
(Controlled Release tablet)

COMPOSITION:
Each ADALAT XL 30 tablet contains 30 mg
nifedipine
Each ADALAT XL 60 tablet contains 60 mg nifedipine

PHARMACOLOGICAL CLASSIFICATION:
A 7.1. Vasodilators, hypotensive medicines.

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. ADALAT XL formulations release nifedipine at an approximately constant rate over 24 hours. The biologically inert components of the tablets remain intact during gastrointestinal transit and are eliminated in the faeces as an insoluble shell.

INDICATIONS:
Treatment of mild to moderate hypertension.
Prophylaxis of chronic stable angina pectoris

CONTRA-INDICATIONS:
ADALAT XL may not be used at any time during pregnancy or lactation or in cases of hypersensitivity to nifedipine, nor must ADALAT XL be used in cardiovascular shock, clinically significant aortic stenosis, unstable angina, or during or within one month of a myocardial infarction.
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.
Owing to the duration of action of the formulation, ADALAT XL should not be administered to patients with hepatic impairment.
ADALAT XL should not be administered to patients with a history of gastrointestinal obstruction, oesophageal obstruction, or any degree of decreased lumen diameter of the gastrointestinal tract.
ADALAT XL is contra-indicated in patients with inflammatory bowel disease.
ADALAT XL is contra-indicated in combination with rifampicin because effective plasma levels of nifedipine may not be obtained because of enzyme induction by rifampicin.
There are no recommendations for use in children.

DOSAGE AND DIRECTIONS FOR USE:
The tablets should be swallowed whole with a glass of fluid; under no circumstances should they be bitten, chewed or broken up. The tablets should be taken at approximately 24 hour intervals, i.e. at the same time each day, preferably during the morning. ADALAT XL may be taken independently of mealtimes.
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.
Patients with renal impairment should not require adjustment of dosage.
A slight alteration of the pharmacokinetics of nifedipine may be seen in the elderly. However, dosage adjustment in these patients is not usually necessary.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
The following side-effects have been observed:
Incidence of frequency >1% and <10%
Body as a whole: Asthenia, edema, headache
Cardiovascular system: Peripheral edema, palpitation, vasodilatation
Digestive system: Constipation
Nervous system: Dizziness
Incidence of frequency >0,1% and <1%
Body as a whole: Abdominal pain, chest pain, leg pain, malaise, pain
Cardiovascular system: Hypotension, postural hypotension, syncope, tachycardia
Digestive system: Diarrhea, dry mouth, dyspepsia, flatulence, nausea
Musculo-skeletal
system:
Leg cramps
Nervous system: Insomnia, nervousness, paresthesia, somnolence, vertigo
Respiratory system: Dyspnea
Skin and appendages: Pruritus, rash
Urogenital system: Nocturia, polyuria
Incidence of frequency >0,01 % and <0,1%
Body as a whole: Allergic reaction, chest pain substernal, chills, face edema, fever
Cardiovascular system: Angina pectoris (excl. unstable), cardiovascular disorder
Digestive system: Anorexia, eructation, gastrointestinal disorder, gingivitis, gum hyperplasia, GGT increased, liver function test abnormal, vomiting
Musculo-skeletal
system:
Arthralgia, joint disorder, myalgia
Nervous system: Hypesthesia, sleep disorder, tremor
Respiratory system: Epistaxis
Skin and appendages: Angioedema, macupopular rash, pustular rash, sweating, urticaria, vesiculobullous rash
Special senses: Abnormal vision, eye disorder, eye pain
Urogenital system: Dysuria, urinary frequency
Others
Incidence of frequency <0,01%
Body as a whole: Anaphylactic reaction
Digestive system: Bezoar, dysphagia, esophagitis, gum disorder, intestinal obstruction, intestinal ulcer, jaundice, SGPT increased
Hemic and lymphatic system: Leucopenia, purpura
Metabolic and nutritional
disorder:
Hyperglycemia, weight loss
Musculo-skeletal system: Muscle cramps
Skin and appendages: Exfoliative dermatitis, gynecomastia, and photosensitive dermatitis
Special senses: Blurred vision
Although a "steal" effect has not been demonstrated, patients experiencing this effect should discontinue nifedipine therapy.
ADALAT XL can enhance or supplement the action of blood pressure lowering preparations such as beta-receptor blockers and diuretics. An additive effect resulting in postural hypotension should be borne in mind. Blood pressure should be monitored carefully during initiation and upward titration of ADALAT XL especially if patients are on antihypertensive therapy.
In dialysis patients with malignant hypertension and hypovolaemia a distinct fall in blood pressure can occur as a result of vasodilation
Special Precautions:
ADALAT XL should not be switched once a patient has been stabilized.
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, in cases of manifest heart failure and in the case of severe aortic stenosis.
A transient increase in blood glucose has been noted. Care must be taken in patients with diabetes mellitus.
ADALAT XL should be used with caution in patients with a poor cardiac reserve.
In single cases obstructive gastrointestinal symptoms have been described without known history of gastrointestinal disorders.
ADALAT XL must not be used in patients with Kock pouch (ileostomy after proctocolectomy).
When doing barium contrast X-ray, ADALAT XL may cause false positive effects (e.g. filling defects interpreted as polyp).
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 to 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 plasmaconcentrations 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
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, severe hypotension, increase or decrease in heart rate, hyperglycaemia, metabolic acidosis, hypoxia, cardiogenic shock with pulmonary oedema and unconsciousness to the point of coma have been observed. 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. Ipecacuanha should be given to children.
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 is 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 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:
Pink lacquered tablets each containing 30 mg or 60 mg nifedipine in a controlled release formulation, marked ADALAT 30 or ADALAT 60.

PRESENTATION:
Blister packs of 28 tablets

STORAGE INSTRUCTIONS:
Store below 25°C.
Protect from light and moisture.
Keep out of reach of children.

REGISTRATION NO.:
ADALAT XL 30:         Y/7.1/314
ADALAT XL 60:         Y/7.1/315

NAME AND BUSINESS ADDRESS OF THE APPLICANT:
BAYER (PTY) LTD
27 Wrench Road        1600        ISANDO

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
21 November 2001

® = Registered Trademark of Bayer AG, Germany

        01143994/DK-ST

Current: March 2005
Source: Hospital Pharmacy

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