Nifedipine Product Monograph

RECENT MAJOR LABEL CHANGES

TABLE OF CONTENTS

Sections or subsections that are not applicable at the time of authorization are not listed.

RECENT MAJOR LABEL CHANGES ............................................................................................. 2

TABLE OF CONTENTS ............................................................................................................... 2

PART I: HEALTH PROFESSIONAL INFORMATION ....................................................................... 4

1 INDICATIONS ................................................................................................................... 4

1.1 Pediatrics ................................................................................................................. 4

1.2 Geriatrics ................................................................................................................. 4

2 CONTRAINDICATIONS ....................................................................................................... 4

4 DOSAGE AND ADMINISTRATION ...................................................................................... 5

4.1 Dosing Considerations ............................................................................................. 5

4.2 Recommended Dose and Dosage Adjustment ........................................................ 5

4.4 Administration ......................................................................................................... 5

4.5 Missed Dose ............................................................................................................ 5

5 OVERDOSAGE ................................................................................................................... 6

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ...................................... 7

7 WARNINGS AND PRECAUTIONS ........................................................................................ 7

7.1 Special Populations................................................................................................ 10

7.1.1 Pregnant Women ............................................................................................ 10

7.1.2 Breast-feeding ................................................................................................. 10

7.1.3 Pediatrics ......................................................................................................... 10

7.1.4 Geriatrics ......................................................................................................... 10

8 ADVERSE REACTIONS ...................................................................................................... 10

8.1 Adverse Reaction Overview ................................................................................... 10

8.2 Clinical Trial Adverse Reactions ............................................................................. 11

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data ............................................................................................................ 13

8.5 Post-Market Adverse Reactions ............................................................................ 13

9 DRUG INTERACTIONS ..................................................................................................... 14

9.1 Serious Drug Interactions ...................................................................................... 14

9.2 Drug Interactions Overview ................................................................................... 14

9.4 Drug-Drug Interactions .......................................................................................... 14

9.5 Drug-Food Interactions .......................................................................................... 21

9.6 Drug-Herb Interactions .......................................................................................... 21

9.7 Drug-Laboratory Test Interactions ......................................................................... 21

10 CLINICAL PHARMACOLOGY ............................................................................................. 21

10.1 Mechanism of Action ............................................................................................. 21

10.2 Pharmacodynamics ............................................................................................... 22

10.3 Pharmacokinetics .................................................................................................. 22

11 STORAGE, STABILITY AND DISPOSAL............................................................................... 23

12 SPECIAL HANDLING INSTRUCTIONS ................................................................................ 23

PART II: SCIENTIFIC INFORMATION ........................................................................................ 24

13 PHARMACEUTICAL INFORMATION ................................................................................. 24

14 CLINICAL TRIALS ............................................................................................................. 24

14.2 Study Results ......................................................................................................... 24

14.3 Comparative Bioavailability Studies ...................................................................... 24

15 MICROBIOLOGY .............................................................................................................. 25

16 NON-CLINICAL TOXICOLOGY ........................................................................................... 25

PATIENT MEDICATION INFORMATION ................................................................................... 28

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

NIFEDIPINE (nifedipine capsules) is indicated for:

• Management of angina resulting from coronary artery spasm.
• Management of chronic stable angina (effort-associated angina) without evidence of vasospasm in patients who remain symptomatic despite adequate doses of beta blockers and/or organic nitrates or who cannot tolerate those agents.

NIFEDIPINE may be used in combination with beta blocking drugs in patients with chronic stable angina, but available information is not sufficient to predict with confidence the effects of concurrent treatment, especially in patients with compromised left ventricular function or cardiac conduction abnormalities. When introducing such concomitant therapy care must be taken to monitor blood pressure closely, since severe hypotension can occur from the combined effects of the drugs (see 7 WARNINGS AND PRECAUTIONS, Cardiovascular).

1.1 Pediatrics

Pediatrics (< 18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

1.2 Geriatrics

Geriatrics (≥ 65 years of age): Evidence from clinical studies and experience suggests that use in the geriatric population is associated with differences in safety or effectiveness (see 4.2 Recommended Dose and Dosage Adjustment, Geriatrics and 7.1.4 Geriatrics).

2 CONTRAINDICATIONS

NIFEDIPINE is contraindicated in:

• Patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, (see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING).
• Patients with a known hypersensitivity to other dihydropyridines calcium antagonists, because of the theoretical risk of cross-reactivity.
• Women who are pregnant, intend to become pregnant, or of childbearing potential who are not using adequate contraception (see 7 WARNINGS AND PRECAUTIONS and 16 NON-CLINICAL TOXICOLOGY, Reproductive and Developmental Toxicology).
• Nursing women (see 7 WARNINGS AND PRECAUTIONS and 16 NON-CLINICAL TOXICOLOGY, Reproductive and Developmental Toxicology).
• Combination with rifampicin because effective plasma levels of nifedipine may not be achieved due to induction of the enzyme metabolizing nifedipine.
• Patients with acute myocardial infarction (see 7 WARNINGS AND PRECAUTIONS, Cardiovascular, Patients with Myocardial Infarction).
• Patients with cardiovascular shock.
• Patients with severe hypotension.

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

• Dosage should be individualized depending on patient tolerance and response.

4.2 Recommended Dose and Dosage Adjustment

The starting dose of NIFEDIPINE is one 10 mg capsule, swallowed whole, 3 times/day. The usual effective dose range is 10 to 20 mg three times daily. Some patients, especially those with evidence of coronary artery spasm, respond only to higher doses, more frequent administration, or both. In such patients, doses of 20 to 30 mg three or four times daily may be effective. A maximum daily dose of 120 mg should not be exceeded.

In general there should be an interval of at least three days between increases in dose in order to adequately assess the response to a particular dose level. In hospitalized patients under close observation the titration phase may proceed more rapidly.

Pediatrics (< 18 years of age)

Health Canada has not authorized an indication for pediatric use (see 7.1.3 Pediatrics).

Geriatrics

NIFEDIPINE should be administered cautiously to elderly patients and the dosage should be carefully and gradually adjusted depending on patient tolerance and response (see 7.1.4 Geriatrics).

Patients with Hepatic Impairment

In patients with impaired liver function, careful monitoring should be performed and a dose reduction may be necessary.

NIFEDIPINE 5 mg capsules provide for greater flexibility of dose titration, e.g. in elderly patients and patients with hepatic impairment.

4.4 Administration

NIFEDIPINE capsules must be swallowed whole.

4.5 Missed Dose

If the patient misses a dose, instruct the patient to take the dose as soon as they remember. If it is almost time for the next dose, inform the patient to skip the missed dose and continue the regular dosing schedule. Do not take a double dose to make up for the forgotten dose.

5 OVERDOSAGE

There are several well documented cases of nifedipine immediate-release overdosage. The following symptoms are observed in cases of severe nifedipine intoxication: disturbance of consciousness to the point of coma, a drop in blood pressure, tachycardia/bradycardia, hyperglycemia, metabolic acidosis, hypoxia, cardiogenic shock with pulmonary edema.

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. Hemodialysis serves no purpose, as nifedipine is not dialysable, but plasmapheresis is advisable (high plasma protein binding, relatively low volume of distribution).

Clinically significant hypotension calls for active cardiovascular support including monitoring of cardiac and respiratory function including elevation of extremities and attention to circulating fluid volume and urine output.

Hypotension as a result of arterial vasodilation can also be treated with calcium (10 mL of 10% calcium gluconate solution administered slowly via intravenous route 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 are additionally administered as a last resort only in patients without cardiac arrhythmia or ischemic heart disease and when other safer measures have failed. 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.

Bradycardia and/or bradyarrhythmias have been observed in some cases of nifedipine overdosage. Appropriate clinical measures, according to the nature and severity of the symptoms, should be applied.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 1 – Dosage Forms, Strengths, Composition and Packaging

NIFEDIPINE (nifedipine) 5 mg: each opaque, mustard colour, oval, soft gelatin capsule, imprinted '5' in white ink with clear, yellow liquid fill, contains nifedipine 5 mg. Available in bottles of 100.

NIFEDIPINE (nifedipine) 10 mg: each opaque, mustard colour, oblong, soft gelatin capsule, imprinted '10' with clear yellow liquid fill, contains nifedipine 10 mg. Available in bottles of 100.

7 WARNINGS AND PRECAUTIONS

General

Concomitant Use with Strong Inhibitors of CYP 3A4

Use of Nifedipine with drugs that result in strong inhibition of CYP 3A4, such as ketoconazole, clarithromycin, ritonavir, may lead to increased plasma levels of nifedipine and associated serious adverse events (see 9 DRUG INTERACTION). Such concomitant use should be avoided.

An observational study demonstrated an increased risk of hospitalization with acute kidney injury when nifedipine was used concomitantly with clarithromycin in elderly patients (>65 years of age) compared to when it was used concomitantly with azithromycin, odds ratio [nifedipine: 5.33 (95% C.I. 3.39 – 8.38)].

Cardiovascular

NIFEDIPINE should be used with care in the following conditions:

Excessive Hypotension

Since NIFEDIPINE lowers peripheral vascular resistance and blood pressure, NIFEDIPINE should be used cautiously in patients who are prone to develop hypotension and those with a history of cerebrovascular insufficiency. Occasional patients have had excessive and poorly tolerated hypotension. Syncope has been reported (see 8.2 Clinical Trial Adverse Reactions, Cardiac disorders). These responses have usually occurred during initial titration or at the time of subsequent upward dosage adjustment, and may be more likely in patients on concomitant beta blockers. If excessive hypotension occurs, dosage should be lowered or the drug should be discontinued (see 2 CONTRAINDICATIONS).

Severe hypotension and/or increased fluid volume requirements have been reported in patients receiving nifedipine together with a beta blocking agent who underwent coronary artery bypass surgery using high dose fentanyl anesthesia. The interaction with high dose fentanyl appears to be due to the combination of nifedipine and a beta blocker, but the possibility that it may occur with nifedipine alone, with low doses of fentanyl, in other surgical procedures, or with other narcotic analgesics cannot be ruled out. In nifedipine treated patients where surgery using high dose fentanyl anesthesia is contemplated, the physician should be aware of these potential problems and, if the patient's condition permits, sufficient time (at least 36 hours) should be allowed for nifedipine to be washed out of the body prior to surgery.

Increased Angina and/or Myocardial Infarction

Rarely, patients, particularly those who have severe obstructive coronary artery disease, have developed well documented increased frequency, duration and/or severity of angina or acute myocardial infarction on starting nifedipine or at the time of dosage increase. The mechanism of this effect is not established.

Patients with Myocardial Infarction

NIFEDIPINE should not be used within one week after myocardial infarction and not before the patient has stabilized. Randomized, placebo-controlled clinical trials have indicated that nifedipine may increase the risk of reinfarction and worsen survival in patients treated early after myocardial infarction (see 2 CONTRAINDICATIONS).

Patients with Unstable Angina

Some clinical trials have shown that treatment with nifedipine in this setting increases the risk of myocardial infarction and recurrent ischemia.

Hypertension

NIFEDIPINE should not be used for the management of essential hypertension.

Acute Reduction of Blood Pressure

NIFEDIPINE should not be used for acute reduction of blood pressure. Strokes have occurred when nifedipine was used in this setting.

Beta Blocker Withdrawal

Patients recently withdrawn from beta blockers may develop a withdrawal syndrome with increased angina, probably related to increased sensitivity to catecholamines. Initiation of nifedipine treatment will not prevent this occurrence and might be expected to exacerbate it by provoking reflex catecholamine release. There have been occasional reports of increased angina in a setting of beta blocker withdrawal and nifedipine initiation. It is important to taper beta blockers if possible, rather than stopping them abruptly before beginning nifedipine.

Patients with Heart Failure

There have been isolated reports of severe hypotension and lowering of cardiac output following administration of nifedipine to patients with severe heart failure. Thus, NIFEDIPINE should be used cautiously in patients with severe heart failure. Rarely, patients usually receiving a beta blocker, have developed heart failure after beginning nifedipine therapy.

In patients with severe aortic stenosis, nifedipine will not produce its usual afterload-reducing effects, and there is a possibility that an unopposed negative inotropic action of the drug may produce heart failure if the end-diastolic pressure is raised. Caution should therefore be exercised when using NIFEDIPINE in patients with these conditions.

Peripheral Edema

Mild to moderate peripheral edema, typically associated with arterial vasodilation and not due to left ventricular dysfunction, has been reported to occur in patients treated with nifedipine (see 8.2 Clinical Trial Adverse Reactions, Cardiac disorders). This edema occurs primarily in the lower extremities and usually responds to diuretic therapy. With patients whose angina is complicated by congestive heart failure, care should be taken to differentiate this peripheral edema from the effects of increasing left ventricular dysfunction.

Driving and Operating Machinery

Reactions to the drug, which vary in intensity from individual to individual, can impair the ability to drive or to operate machinery, particularly at the start of the treatment, upon changing the medication, or in combination with alcohol. Exercise caution when driving or operating a vehicle or potentially dangerous machinery.

Endocrine and Metabolism

Use in Diabetic Patients

The use of NIFEDIPINE in diabetic patients may require adjustment of their blood glucose control.

Hepatic/Biliary/Pancreatic

Use in Patients with Impaired Liver Function

NIFEDIPINE should be used with caution in patients with impaired liver function (see 10.3 Pharmacokinetics, Special Populations and Conditions, Hepatic insufficiency). A dose reduction, may be required. The response and metabolic effect should be monitored closely.

Monitoring and Laboratory Tests

Hypotension/Heart Rate

Because NIFEDIPINE is an arterial and arteriolar vasodilator, hypotension and a compensatory increase in heart rate may occur. Thus, blood pressure and heart rate should be monitored carefully during nifedipine therapy. Close monitoring is especially recommended for patients who are prone to develop hypotension, those with a history of cerebrovascular insufficiency, and those who are taking medications that are known to lower blood pressure (see 7 WARNINGS AND PRECAUTIONS, Cardiovascular).

Reproductive Health: Female and Male Potential

Male Fertility

In some cases of in vitro fertilization, nifedipine has been associated with reversible spermatozoal biochemical changes. In vitro studies have shown that nifedipine may inhibit expression of mannose-ligand receptors, thus preventing the spermatozoa from attaching to the zona pellucida and impairing sperm function. In those men who are repeatedly unsuccessful in fathering a child by in vitro fertilization, and where no other explanation could be found, nifedipine should be considered as a possible cause.

Women of Child-bearing Potential/Contraception

NIFEDIPINE may cause embryo-fetal harm when administered during pregnancy. Women of child-bearing potential should use effective contraception during treatment with NIFEDIPINE (see 7.1.1 Pregnant Women and 16 NON-CLINICAL TOXICOLOGY).

7.1 Special Populations

7.1.1 Pregnant Women

NIFEDIPINE is contraindicated during pregnancy. Fetal malformations and adverse effects on pregnancy have been reported in animals. An increase in the number of fetal mortalities and resorptions occurred after the administration of 30 and 100 mg/kg nifedipine to pregnant mice, rats and rabbits. Fetal malformations occurred after the administration of 30 and 100 mg/kg nifedipine to pregnant mice and 100 mg/kg to pregnant rats (see 2 CONTRAINDICATIONS).

7.1.2 Breast-feeding

NIFEDIPINE is contraindicated in use during breast-feeding (see 2 CONTRAINDICATIONS).

7.1.3 Pediatrics

Pediatrics (< 18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

7.1.4 Geriatrics

Geriatrics (≥ 65 years of age): NIFEDIPINE should be administered cautiously to elderly patients, especially to those with a history of hypotension or cerebral vascular insufficiency (see 4.2 Recommended Dose and Dosage Adjustment, Geriatrics).

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

The most common adverse effects, which generally result from the vasodilating effects of nifedipine were: headache (7.2%); dizziness, lightheadedness and giddiness (6.7%), nausea and vomiting and gastrointestinal distress (6.7%); flushing and heat sensation (5.8%); peripheral edema (3.7%) and hypotension (2.0%).

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

A safety analysis from the world literature (controlled and open studies) was carried out in a heterogeneous group of 7146 patients who were treated with nifedipine. Adverse effects were reported in 27.9% of patients and required discontinuation of treatment in 5.5% of patients.

As a part of the above analysis, a more comprehensive safety evaluation (controlled and open studies) was carried out in 3074 patients, some of whom were severely ill and were receiving a variety of concomitant drugs, such as beta-blockers, nitrates, antiarrhythmics, cardiac glycosides, diuretics and anti-platelet drugs, etc.

The following adverse effects divided by systems were reported in these 3074 patients:

Cardiac disorders

Common (≥1% and <10%):

Peripheral edema: 8.3%

Palpitation and increased heart rate: 2.6%

Uncommon (≥0.1% and <1%):

Syncope: 0.4%

Rarely (≥0.01% and ≤1%), and possibly due to tachycardia, nifedipine has been reported to have precipitated an angina pectoris attack. In addition, more serious events were occasionally observed, not readily distinguishable from the natural history of the disease in these patients. It remains possible, however, that some or many of these events were drug related. These events include myocardial infarction, congestive heart failure or pulmonary edema, and ventricular arrhythmias or conduction disturbances.

Eye disorders

Uncommon (≥0.1% and <1%):

Blurred vision: 0.9%

Gastrointestinal disorders

Common (≥1% and <10%):

Nausea and vomiting: 6.4%

Abdominal discomfort and heartburn: 2.0%

Uncommon (≥0.1% and <1%):

Diarrhea: 0.9%

Constipation: 0.6%

General disorders and administration site conditions

Common (≥1% and <10%):

Swelling: 8.3%

Heat sensation: 7.4%

General weakness: 6.3%

Jitteriness: 1.9%

Fever, sweating and chills: 1.4%

Metabolism and nutrition disorders

Common (≥1% and <10%):

Fluid retention: 8.3%

Musculoskeletal and connective tissue disorders

Common (≥1% and <10%):

Joint stiffness, muscle pain and cramps: 4.3%

Nervous system disorders

Very common (≥10%):

Dizziness, lightheadedness, giddiness: 11.9%

Common (≥1% and <10%):

Headache: 7.8%

Shakiness, nervousness: 1.9%

Sleep disturbances: 1.1%

Psychiatric disorders

Uncommon (≥0.1% and <1%):

Depression: 0.6%

Respiratory, thoracic and mediastinal disorders

Common (≥1% and <10%):

Shortness of breath, dyspnea: 1.3%

Uncommon (≥0.1% and <1%):

Nasal congestion: 0.5%

Skin and subcutaneous tissue disorders

Common (≥1% and <10%):

Pruritus, dermatitis, urticaria and rash: 1.9%

Vascular disorders:

Common (≥1% and <10%):

Flushing: 7.4%

Hypotension: 3.5%

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

Laboratory Tests

Rarely, mild to moderate transient elevations of enzymes such as alkaline phosphatase, Creatine phosphokinase (CPK), Lactate dehydrogenase (LDH), Serum Glutamic Oxaloacetic Transaminase (SGOT) and Serum Glutamic Pyruvic Transaminase (SGPT) have been noted after treatment with nifedipine. These laboratory abnormalities have rarely been associated with clinical symptoms, however, cholestasis with or without jaundice has been reported. Infrequent reversible elevations in Blood Urea Nitrogen (BUN) and serum creatinine have been reported in patients with pre-existing chronic renal insufficiency taking nifedipine.

8.5 Post-Market Adverse Reactions

The following adverse events have been reported with nifedipine rarely (≥0.01% and ≤1%).

Rare instances of allergic hepatitis and cholestasis with or without jaundice have been reported in patients treated with nifedipine.

Gingival hyperplasia similar to that caused by diphenylhydantoin has been reported in patients treated with nifedipine. The lesions usually regressed on discontinuation of the drug. However, on occasion gingivectomy was necessary.

Gynecomastia has been observed rarely in older men on long-term therapy, but has so far always regressed completely on discontinuation of the drug.

Isolated cases of angioedema have been reported. Angioedema may be accompanied by breathing difficulty. Anaphylaxis has been reported rarely.

In post marketing experience, there have been rare reports of exfoliative dermatitis and Stevens-Johnson Syndrome. Gastrointestinal irritation and gastrointestinal bleeding were also reported; however, the causal relationship is uncertain.

The following adverse events were identified only during post marketing experience with a frequency that could not be estimated: agranulocytosis, epidermal photosensitivity allergic reaction, eye pain, gastro esophageal sphincter insufficiency, hyperglycemia, hypoesthesia, jaundice, leukopenia, toxic epidermal necrolysis, somnolence, toxic palpable purpura, intestinal obstruction, bezoars.

9 DRUG INTERACTIONS

9.1 Serious Drug Interactions

9.2 Drug Interactions Overview

As with all drugs, care should be exercised when treating patients with multiple medications. Dihydropyridine calcium channel blockers undergo biotransformation by the cytochrome P450 system, mainly via the CYP 3A4 isoenzyme. Coadministration of nifedipine with other drugs which follow the same route of biotransformation may result in altered bioavailability. Dosages of similarly metabolized drugs, particularly those of low therapeutic ratio, and especially in patients with renal and/or hepatic impairment, may require adjustment when starting or stopping concomitantly administered nifedipine to maintain optimum therapeutic blood levels.

9.4 Drug-Drug Interactions

The drugs listed in this table are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated).

Table 2 - Established or Potential Drug-Drug Interactions

Legend: C = Case Study CT = Clinical Trial; T = Theoretical

9.5 Drug-Food Interactions

Interaction with Grapefruit Juice: Published data indicate that through inhibition of cytochrome P450, grapefruit juice can increase plasma levels and augment pharmacodynamic effects of some dihydropyridine calcium channel blockers, including nifedipine (see 10.3 Pharmacokinetics, Special Populations and Conditions, Grapefruit juice). Therefore, consumption of grapefruit juice prior to or during treatment with nifedipine should be avoided.

9.6 Drug-Herb Interactions

Hypericum perforatum – Saint John's Wort is an inducer of CYP3A4 and has been shown to cause a decrease in plasma concentrations of nifedipine. Therefore, dosage of nifedipine may have to be increased.

9.7 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

NIFEDIPINE (nifedipine) is a calcium ion influx inhibitor (calcium entry blocker or calcium ion antagonist). The anti-anginal effect of this group of drugs is believed to be related to their specific cellular action of selectively inhibiting transmembrane influx of calcium ions into cardiac muscle and vascular smooth muscle. The contractile processes of these tissues are dependent upon the movement of extra-cellular calcium into the cells through specific ion channels. Nifedipine blocks the transmembrane influx of calcium through the slow channels without affecting to any significant degree the transmembrane influx of sodium through the fast channel. This results in a reduction of free calcium ions available within cells of the above tissues. Nifedipine does not alter total serum calcium.

The specific mechanism by which nifedipine relieves angina has not been fully determined but it is believed to be brought about largely by its vasodilatory action.

10.2 Pharmacodynamics

Nifedipine dilates the main coronary arteries and coronary arterioles both in normal and ischemic regions and is a potent inhibitor of coronary artery spasm. This property increases myocardial oxygen delivery and is responsible for the effectiveness of nifedipine in vasospastic angina.

Nifedipine, by its vasodilatory action on peripheral arterioles, reduces the total peripheral vascular resistance. This reduces the workload of the heart and thus reduces the myocardial energy consumption and oxygen requirements and probably accounts for the effectiveness of nifedipine in chronic stable angina.

The negative inotropic effect of nifedipine is usually not of major clinical significance because the drug's vasodilating properties evoke at therapeutic doses a baroreceptor-mediated reflex tachycardia which tends to counterbalance this negative inotropic effect.

Although nifedipine causes a slight depression of sinoatrial node function and atrioventricular conduction in isolated myocardial preparations, such effects have not been seen in studies in intact animals or man. In formal electrophysiologic studies, predominantly in patients with normal conduction systems, nifedipine has no tendency to prolong atrioventricular conduction or sinus node recovery time, or to slow sinus rate.

Inhibition of Transmembrane Ca⁺⁺ Influx

Nifedipine has been shown in isolated preparations to restrict the transmembrane calcium ion influx during excitation-contraction coupling in both cardiac and vascular smooth muscles.

10.3 Pharmacokinetics

Absorption

In human, oral administration of 10 mg ¹⁴C nifedipine resulted in more than 90% absorption of the drug. Radioactivity was detectable in the serum 20 minutes after oral ingestion and peak serum levels were reached in 1 to 2 hours. 70 to 80% of the activity was eliminated via the kidneys and the remainder via the feces.

The bi-exponential analysis of the disappearance of nifedipine in the plasma yields an initial fast half- life (t½ß) of 2.5 to 3 hours and a terminal slow half-life (t½α) of 5 hours.

Distribution

Protein binding of circulating nifedipine exceeds 90%.

Metabolism

Nifedipine is metabolized by the cytochrome P450 enzyme system, predominantly via CYP 3A4, but also by CYP 1A2 and CYP 2A6 isoenzymes.

Studies in human, dog and rat showed that nifedipine is almost completely metabolized in the body. It is transformed into two pharmacologically inactive metabolites. The main metabolite is the hydroxycarboxylic acid derivative which represents about 95%, the other is the corresponding lactone, which represents about 5%.

Compounds found in grapefruit juice inhibit the cytochrome P450 system, especially isoenzyme CYP 3A4. In a grapefruit juice-nifedipine interaction study in healthy male volunteers, pharmacokinetics of nifedipine showed significant alteration. Following administration of a single dose of nifedipine 10 mg with 250 mL of grapefruit juice, the mean value of nifedipine AUC increased by 34% and the T_max increased from 0.8 hours to 1.2 hours, as compared to water (see 9.5 Drug-Food Interactions, Interaction with Grapefruit Juice).

Elimination

The acid form is mainly excreted in the urine. The remainder is excreted in the feces in metabolized form, most likely as a result of biliary excretion.

Special Populations and Conditions

• Hepatic Insufficiency: Since hepatic biotransformation is the predominant route for the disposition of nifedipine, the pharmacokinetics may be altered in patients with chronic liver disease. Pharmacokinetic studies in patients with hepatic cirrhosis showed a clinically significant alteration in the kinetics of nifedipine (prolonged elimination half life and decreased total clearance). The degree of serum protein binding of nifedipine is high (92-98%). Protein binding may be greatly reduced in patients with hepatic impairment. In these patients, there is a considerable risk of accumulation (see 7 WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic).

• Renal Insufficiency

  The pharmacokinetics of nifedipine are not significantly influenced by the degree of renal impairment. Patients in hemodialysis or CAPD (continuous ambulatory peritoneal dialysis) have not reported significantly altered pharmacokinetics of nifedipine.

11 STORAGE, STABILITY AND DISPOSAL

The capsules should be stored between 15°C and 25°C. Avoid freezing. Protect from light.

NIFEDIPINE should never be disposed of in household trash. Disposal via a pharmacy take back program is recommended.

Keep out of reach and sight of children.

12 SPECIAL HANDLING INSTRUCTIONS

None.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Nifedipine

Chemical name: 1,4-dihydro-2,6-dimethy1-4-(2-nitropheny1)-3,5-pyridine-dicarboxylic acid dimethyl ester

Molecular formula and molecular mass: C₁₇H₁₈N₂0₆ and 346.3 g/mol

Structural formula:

Physicochemical properties: Nifedipine is a pyridine dicarboxylic acid dimethylester. It is a fine yellowish powder, practically insoluble in water but soluble in ethanol. It is light-sensitive, and when exposed, is converted to a pharmacologically inactive pyridine derivative via an intramolecular redox process.

14 CLINICAL TRIALS

14.2 Study Results

See 14.3 Comparative Bioavailability Studies

14.3 Comparative Bioavailability Studies

A randomized, two treatment, single-dose, crossover comparative bioavailability study of APO-NIFEDIPINE 10 mg Capsule (Apotex Inc.) with ADALAT 10 mg Capsule (Miles Canada Inc.) was conducted in healthy, adult, male subjects under fasting conditions. Comparative bioavailability data from the 24 subjects that were included in the statistical analysis are presented in the following table:

Table 3 - Summary Table of the Comparative Bioavailability Data

¹ Apo-Nifedipine 10 mg Capsule (Apotex Inc.)

²Adalat 10 mg Capsule (Miles Canada Inc.)

³ Expressed as the median (range) only

⁴ Expressed as arithmetic means (CV%) only.

15 MICROBIOLOGY

No microbiological information is required for this drug product.

16 NON-CLINICAL TOXICOLOGY

General Toxicology

Acute Toxicity Studies

Table 4 - Oral LD₅₀ Values of Nifedipine

¹ Identity of the test product.

² Identity of the reference product, including the manufacturer, and origin (country of purchase).

The oral LD₅₀ of nifedipine in albino mice was calculated to be 1000 mg/kg regardless of sex; in rats 6200 mg/kg and 4300 mg/kg for males and females respectively.

In mice, most deaths occurred within 24 hours of dosing while in rats, deaths occurred between days 2 and 9 post-dosing. In mice, principal signs of toxicity included ptosis, piloerection, hunching of the back, dyspnea, abdominal distention, tremor and reduced motor activity. In rats, principal signs of toxicity included darkening of the liver, spleen and/or G.I. tract, reddening of the lungs, adrenals, thymus and/or intestines, G.I. tract distention and in some animals, ascites. In both species, animals killed routinely at the end of the studies revealed no abnormalities upon necropsy.

Subacute Toxicity Studies

In rats, oral doses of 0.5 to 100 mg/kg/day nifedipine for 13 weeks did not induce significant adverse effects. Similar results were obtained in dogs treated with 0.5 to 50 mg/kg/day nifedipine for 13 weeks.

Carcinogenicity

Nifedipine was administered orally to dogs at dosages of 2.5, 20 and 100 mg/kg/day for 52 weeks. No indication of toxic damage caused by nifedipine was found.

In a 2–year study, nifedipine was administered orally to male and female rats in the diet at dosages of 5 to 9, 29 to 39, and 156 to 210 mg/kg/day. In the lowest dose group, nifedipine was without toxic effects. The higher dosage led to dose-dependent, significant weight losses. An increased mortality was found in the 156 to 210 mg/kg dose group, especially in the females. The pathological- anatomical examination of the dead animals showed a hypotonia or atonia of the musculature of the small intestine. An increase in the weight of the adrenal glands of male rats was also observed in this dose group. Histopathological examinations revealed no organ damage related to treatment.

At the end of the study, all rats were examined histopathologically with regards to tumorigenesis. Although the animals in the highest dose group showed no uncommon tumor incidences, this group was considered not suitable for comparison with the other treatment groups because of the high mortality rate. No significant difference were found between the controls and the remaining two treatment groups with respect to the frequency, nature and localization of tumors.

Genotoxicity

Mutagenicity Studies

In the Dominant Lethal test, the oral administration of nifedipine to mice at a dose of 100 mg/kg for 5 consecutive days did not affect fertility rate or post-implantation loss.

In the Micronucleus test, 2 doses of 50 mg/kg or 100 mg/kg nifedipine given orally to mice also did not produce any mutagenic effect. Furthermore, the formation of erythrocytes was not impaired as shown by the polychromatic: normochromatic erythrocyte ratio.

In the Ames' Salmonella/microsome test, nifedipine at doses of up to 12500 mcg per plate did not cause any bacterotoxic effects. Also, a dose-dependent and biologically relevant increase in the number of mutants to a level double that of the negative control was not noted.

Reproductive and Developmental Toxicology

Pregnant mice, rats and rabbits were treated orally with 10, 30 and 100 mg/kg nifedipine from day 6 to day 15 of gestation. In the mouse, at doses of 30 and 100 mg/kg there was an increase in the number of fetal resorptions. Fetal malformations in the form of cleft palate and rib deformities occurred at all dose levels in a dose related fashion. (Cleft palate occurred in 5/218 controls, 13/190 at 10 mg/kg, 22/112 at 30 mg/kg and 3/3 at 100 mg/kg).

In the rat, the dose of 30 mg/kg was not toxic to pregnant dams, but caused reduced fetal weight and increased fetal loss. The dose of 100 mg/kg produced malformations in the fetuses from 20% of the mother animals. In a total of 11 fetuses, 10 showed malformation of the front or hind paws (ectrodactyly, oligodactyly and adactyly) and one developed a severe malformation of the sinciput.

In the rabbit, there was a dose-dependent anorexia and weight loss in mothers during the dosing period. At 30 and 100 mg/kg, reduced litter size and weight and increased fetal loss were evident.

Studies on pregnant rhesus monkeys with oral doses of 2 (1 animal) or 6 mg/kg/day (4 animals) revealed no teratogenic effects. The placentas were poorly developed in dosed animals.

Pre- and post-natal studies on rats with daily doses of 3, 10, 30 and 100 mg/kg showed that nifedipine caused significant prolongation of the gestation period at dosage of 10 mg/kg upwards and a decrease in litter size. The post-natal development of the newborn animals was impaired when doses of 30 mg/kg or more had been administered. All offspring in the 100 mg/kg group died.