Trinipatch 0.2 Product Monograph

RECENT MAJOR LABEL CHANGES

TABLE OF CONTENTS

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 ................................. 6

7 WARNINGS AND PRECAUTIONS .................................................................................. 8

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

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

7.1.2 Breast-feeding ................................................................................................ 11

7.1.3 Pediatrics ........................................................................................................ 11

7.1.4 Geriatrics ........................................................................................................ 11

8 ADVERSE REACTIONS ................................................................................................ 11

8.1 Adverse Reaction Overview .................................................................................. 11

8.5 Post-Market Adverse Reactions ........................................................................... 11

9 DRUG INTERACTIONS ................................................................................................ 12

9.1 Serious Drug Interactions ..................................................................................... 12

9.2 Drug Interactions Overview .................................................................................. 12

9.3 Drug-Behavioural Interactions .............................................................................. 12

9.4 Drug-Drug Interactions ......................................................................................... 12

9.5 Drug-Food Interactions ......................................................................................... 14

9.6 Drug-Herb Interactions ......................................................................................... 14

9.7 Drug-Laboratory Test Interactions ........................................................................ 14

10 CLINICAL PHARMACOLOGY ....................................................................................... 14

10.1 Mechanism of Action ...................................................................................... 14

10.2 Pharmacodynamics ........................................................................................ 15

10.3 Pharmacokinetics ........................................................................................... 15

11 STORAGE, STABILITY AND DISPOSAL ......................................................................... 16

12 SPECIAL HANDLING INSTRUCTIONS ........................................................................... 16

PART II: SCIENTIFIC INFORMATION ....................................................................................... 17

13 PHARMACEUTICAL INFORMATION ............................................................................ 17

14 CLINICAL TRIALS ........................................................................................................ 17

14.1 Clinical Trials by Indication ............................................................................. 17

14.2 Comparative Bioavailability Studies ................................................................ 17

15 MICROBIOLOGY ........................................................................................................ 18

16 NON-CLINICAL TOXICOLOGY ..................................................................................... 18

PATIENT MEDICATION INFORMATION .................................................................................. 20

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

TRINIPATCH (nitroglycerin) used intermittently (see 10 CLINICAL PHARMACOLOGY) is indicated for the prevention of anginal attacks in patients with stable angina pectoris associated with coronary artery disease. It can be used in conjunction with other antianginal agents such as beta-blockers and/or calcium antagonists.

TRINIPATCH is not intended for the immediate relief of acute attacks of angina pectoris. Sublingual nitroglycerin preparations should be used for this purpose.

1.1 Pediatrics

No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

1.2 Geriatrics

No special information is available on the use of TRINIPATCH in geriatric population. However, there is no evidence suggesting that dosage should be adapted in these patients.

2 CONTRAINDICATIONS

• TRINIPATCH (nitroglycerin) is contraindicated in patients who are hypersensitive to this drug and related organic nitrate compounds or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the patch. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.

• TRINIPATCH (nitroglycerin) is contraindicated in patients with:

  • Acute circulatory failure associated with marked hypotension (shock and states of collapse).
  • Postural hypotension.
  • Left ventricular dysfunction due to obstruction as in aortic or mitral stenosis or of constrictive pericarditis.
  • Increased intracranial pressure.
  • Increased intraocular pressure.
  • Severe anemia.
• Concomitant use of TRINIPATCH (nitroglycerin) either regularly and/or intermittently, with phosphodiesterase type 5 (PDE5) inhibitors such as VIAGRA^® (sildenafil), CIALIS^® (tadalafil) and LEVITRA^® (vardenafil) is absolutely contraindicated, because PDE5 inhibitors amplify the vasodilatory effects of TRINIPATCH which can lead to severe hypotension. See 7 WARNINGS AND PRECAUTIONS and 9 DRUG INTERACTIONS.

• Do not use TRINIPATCH (nitroglycerin) in patients who are taking the soluble guanylate cyclase stimulator ADEMPAS® (riociguat) for chronic thromboembolic pulmonary hypertension or pulmonary arterial hypertension. Concomitant use can cause hypotension. See

  7 WARNINGS AND PRECAUTIONS and 9 DRUG INTERACTIONS.

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

The daily dosage schedule is based on intermittent therapy to prevent the development of tolerance to nitroglycerin. The optimal dose should be selected based upon the clinical response, side effects, and the effects of therapy on blood pressure (see 7 WARNINGS AND PRECAUTIONS).

4.2 Recommended Dose and Dosage Adjustment

Starting dose is one TRINIPATCH 0.2 patch (7 cm²), usually applied in the morning. If 0.2 mg/hour (7 cm²) is well tolerated, the dose can be increased to 0.4 mg/hour (14 cm²) if required. A maximum of 0.8 mg/hour may be used.

Considerations for Special Populations

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

Geriatric (>65 years of age): No special information is available on the use of TRINIPATCH in geriatric population. However, there is no evidence suggesting that dosage should be adapted in these patients.

4.4 Administration

TRINIPATCH can be applied to any area of skin except the distal extremities. Many patients prefer the chest. Each successive application should be to a different site.

The area should be clean, dry, and preferably hairless. If hair is likely to interfere with patch adhesion or removal, clipping may be necessary prior to application. Take care to avoid areas with cuts or irritations. TRINIPATCH should be applied for 12-14 hours and taken off for 10-12 hours. Maximum daily dose is 0.8 mg/hour.

Following use, the patch should be discarded in a manner that prevents accidental application or ingestion.

4.5 Missed Dose

If the patient has forgotten to apply TRINIPATCH at the scheduled time then they should apply it as soon as possible. However, if it is almost time for the next dose, the missed dose should be skipped and the patient should go back to their regular dosing schedule. The patient should not apply extra patches to make up for a missed dose.

5 OVERDOSAGE

Symptoms

Nitroglycerin overdose may result in severe hypotension, persistent throbbing headache, vertigo, palpitations, visual disturbances, flushing and perspiring skin (later becoming cold and cyanotic), anorexia, nausea and vomiting (possibly with colic and even bloody diarrhea), syncope (especially in the upright posture), methemoglobinemia with cyanosis, hyperpnea, dyspnea and slow breathing, slow pulse (dicrotic and intermittent), heart block and bradycardia, increased intracranial pressure with cerebral symptoms of fever, confusion, and coma possibly followed by paralysis, clonic convulsions and death due to circulatory collapse.

Treatment

Keep the patient recumbent in a shock position and comfortably warm. Remove the TRINIPATCH.

Passive movement of the extremities may aid venous return. Administer oxygen and artificial ventilation if necessary.

Intravenous infusion of normal saline or similar fluid may also be required to produce sufficient central volume expansion. However, in patients with renal disease or congestive heart failure, therapy resulting in central volume expansion is not without hazard. Treatment of nitroglycerin overdose in these patients may be subtle and difficult, and invasive monitoring may be required.

Epinephrine is ineffective in reversing the severe hypotensive events associated with overdose; it and related compounds are contraindicated in this situation.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 1 – Dosage Forms, Strengths, Composition and Packaging

Composition

The TRINIPATCH (nitroglycerin) transdermal system is a flat unit designed to provide continuous controlled release of nitroglycerin through intact skin. The rate of release of nitroglycerin is linearly dependent upon the area of the applied system; each cm² of applied system delivers approximately 0.03 mg of nitroglycerin per hour. Thus, the 7, 14 and 21 cm² systems deliver approximately 0.2, 0.4 and 0.6 mg of nitroglycerin per hour, respectively.

The remainder of the nitroglycerin in each system serves as a reservoir and is not delivered in normal use. After 12 hours, for example, each system has delivered approximately 10% of its original content of nitroglycerin.

The TRINIPATCH system comprises three layers:

1. 1. a thin, occlusive, low density polyethylene (LDPE) backing film layer,
2. 2. an acrylic adhesive matrix/drug reservoir layer,
3. 3. a layer of siliconized polyester release liner comprised of overlapped liner strips that form an easy-opening tab.

Prior to use, a protective peel strip is removed from the adhesive surface.

Cross-section of the system.

1. 1. Low density polyethylene (LDPE) Backing Film
2. 2. Matrix Adhesive Layer
3. 3. Overlapped Release Liner Strips, Peel Tab

Dosage Forms and Packaging

Each TRINIPATCH 0.2 (7 cm²) contains 22.4 mg of nitroglycerin and delivers approximately 0.2 mg of active substance per hour.

Strength/Composition

Each TRINIPATCH 0.4 (14 cm²) contains 44.8 mg of nitroglycerin and delivers approximately 0.4 mg of active substance per hour.

Each TRINIPATCH 0.6 (21 cm²) contains 67.2 mg of nitroglycerin and delivers approximately 0.6 mg of active substance per hour.

Available in boxes of 30 and 100 systems. Each system is individually sealed in a separate pouch.

7 WARNINGS AND PRECAUTIONS

General

Daily headaches sometimes accompany treatment with nitroglycerin. In patients who get these headaches, the headaches may be a marker of the activity of the drug. Patients should resist the temptation to avoid headaches by altering the schedule of their treatment with nitroglycerin, since loss of headache may be associated with simultaneous loss of antianginal efficacy.

After normal use, there is enough residual nitroglycerin in discarded patches that they are a potential hazard to children and pets.

Carcinogenesis and Mutagenesis

See 16 NON-CLINICAL TOXICOLOGY.

Cardiovascular

TRINIPATCH must be removed before cardioversion or DC defibrillation is attempted, as well as before applying diathermy treatment.

The benefits and safety of transdermal nitroglycerin in angina patients with acute myocardial infarction or congestive heart failure have not been established. If one elects to use TRINIPATCH in these conditions, careful clinical or hemodynamic monitoring must be used to avoid the potentially deleterious effects of induced hypotension and tachycardia.

Headaches or symptoms of hypotension, such as weakness or dizziness, particularly when arising suddenly from a recumbent position, may occur. A reduction in dose or discontinuation of treatment may be necessary.

Caution should be exercised when using nitroglycerin in patients prone to, or who might be affected by hypotension. The drug therefore should be used with caution in patients who may have volume depletion from diuretic therapy or in patients who have low systolic blood pressure (e.g. below 90 mmHg). Paradoxical bradycardia and increased angina pectoris may accompany nitroglycerin-induced hypotension.

Nitrate therapy may aggravate the angina caused by hypertrophic cardiomyopathy.

Concomitant use of TRINIPATCH (nitroglycerin) either regularly and/or intermittently, with phosphodiesterase type 5 (PDE5) inhibitors such as VIAGRA^® (sildenafil), CIALIS^® (tadalafil) and LEVITRA

^® (vardenafil) is absolutely contraindicated, because PDE5 inhibitors amplify the vasodilatory effects of TRINIPATCH which can lead to severe hypotension. See 2 CONTRAINDICATIONS and 9 DRUG INTERACTIONS.

Do not use TRINIPATCH (nitroglycerin) in patients who are taking the soluble guanylate cyclase stimulator ADEMPAS® (riociguat) for chronic thromboembolic pulmonary hypertension or pulmonary arterial hypertension. Concomitant use can cause hypotension. See 2 CONTRAINDICATIONS and 9 DRUG INTERACTIONS.

Dependence/Tolerance

In industrial workers who have had long-term exposure to unknown (presumably high) doses of nitroglycerin, tolerance clearly occurs. There is moreover, physical dependence since chest pain, acute myocardial infarction, and even sudden death have occurred during temporary withdrawal of nitroglycerin from these workers. In clinical trials of angina patients, there are reports of anginal attacks being more easily provoked and of rebound in the hemodynamic effects soon after nitrate withdrawal. The importance of these observations to the routine clinical use of nitroglycerin has not been fully elucidated, but patients should be monitored closely for increased anginal symptoms during drug-free periods.

Tolerance to nitroglycerin with cross tolerance to other nitrates or nitrites may occur. Co-administration of other long-acting nitrates could jeopardize the integrity of the nitrate-free interval and therefore must be avoided. As tolerance to nitroglycerin patches develops, the effect of sublingual nitroglycerin on exercise tolerance, although still observable, is somewhat blunted.

Prevention of tolerance

Although some controlled clinical trials using exercise tolerance testing have shown maintenance of effectiveness when patches are worn continuously, the large majority of such controlled trials have shown the development of tolerance (i.e. complete loss of effect) within the first 24 hours after therapy was initiated. Dose adjustments even to levels much higher than generally used did not prevent the development of tolerance. Tolerance has appeared even when doses greater than 4 mg/hour were delivered continuously, a dose far in excess of the effective dose 0.2 to 0.8 mg/hour applied intermittently.

Efficacy of organic nitrates is restored after a period of absence of nitrates from the body. Thus, tolerance can be prevented or attenuated by use of an intermittent dosage schedule. Although the minimum nitrate-free interval has not been defined, clinical trials have demonstrated that an appropriate dosing schedule for nitroglycerin patches would provide for a daily patch-on period of 12 - 14 hours and a daily patch-off period of 10 - 12 hours. The patch-free time should coincide with the period in which angina pectoris is least likely to occur (usually at night). Patients should be watched carefully for an increase of angina pectoris during the patch-free period. Adjustment of background medication may be required.

Several studies have demonstrated that when nitroglycerin is administered according to an intermittent regimen, doses of 0.4 - 0.8 mg/hr have increased exercise capacity for up to 8 hours, with a trend of increased exercise capacity to 12 hours. One controlled clinical trial suggested that the intermittent use of nitrates may be associated with a decreased exercise tolerance, in comparison to placebo, during the last part of the nitrate-free interval; the clinical relevance of this observation is unknown, but the possibility of increased frequency or severity of angina during the nitrate-free interval should be considered.

The dose of TRINIPATCH should be periodically reviewed in relation to continuing antianginal control.

Driving and Operating Machinery

As patients may experience faintness and/or dizziness, reaction time when driving or operating machinery may be impaired, especially at the start of treatment.

Hematologic

Case reports of clinically significant methemoglobinemia are rare at conventional doses of nitroglycerin. The formation of methemoglobin is dose-related, and in the case of genetic abnormalities of hemoglobin that favour methemoglobin formation, even conventional doses of organic nitrates can produce harmful concentrations of methemoglobin. Methemoglobin levels are available from most clinical laboratories. The diagnosis should be suspected in patients who exhibit signs of impaired oxygen delivery despite adequate cardiac output and adequate arterial pO₂. Classically, methemoglobinemic blood is described as chocolate brown, without color change on exposure to air. If methemoglobinemia is present, administration of methylene blue (1% solution), 1 to 2 mg/kg intravenously, may be required.

Neurologic

Treatment with nitroglycerin may be associated with lightheadedness on standing, especially just after rising from a recumbent or seated position. This effect may be more frequent in patients who have also consumed alcohol.

Respiratory

Caution should be exercised in patients with arterial hypoxemia due to anemia (see 2 CONTRAINDICATIONS), because in such patients the biotransformation of nitroglycerin is reduced. Similarly, caution is called for in patients with hypoxemia and ventilation/perfusion imbalance due to lung disease or ischemic heart failure. Patients with angina pectoris, myocardial infarction, or cerebral ischemia frequently suffer from abnormalities of the small airways (especially alveolar hypoxia). Under these circumstances vasoconstriction occurs within the lung to shift perfusion from areas of alveolar hypoxia to better ventilated regions of the lung. As a potent vasodilator, nitroglycerin could reverse this protective vasoconstriction and thus result in increased perfusion to poorly ventilated areas, worsening of the ventilation/perfusion imbalance, and a further decrease in the arterial partial pressure of oxygen.

7.1 Special Populations

7.1.1 Pregnant Women

Animal reproduction studies have not been conducted with nitroglycerin. It is not known whether nitroglycerin can cause fetal harm when administered to a pregnant woman. Therefore use TRINIPATCH only if the potential benefit justifies the risk to the fetus.

7.1.2 Breast-feeding

It is not known whether nitroglycerin is excreted into breast milk. Benefits to the mother must be weighed against the risks to the child.

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): No special information is available on the use of TRINIPATCH in geriatric population. However, there is no evidence suggesting that dosage should be adapted in these patients.

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

Headache, which may be severe, is the most commonly reported side effect. Headache may be recurrent with each daily dose, especially at higher doses of nitroglycerin. Headaches may be treated with concomitant administration of mild analgesics. If such headaches are unresponsive to treatment, the nitroglycerin dosage should be reduced or the product discontinued. Transient episodes of lightheadedness, occasionally related to blood pressure changes, may also occur. Hypotension occurs infrequently, but in some patients it may be severe enough to warrant discontinuation of therapy.

Reddening of the skin (erythema), with or without a mild local itching (pruritus) or burning sensation, as well as allergic contact dermatitis may occasionally occur. Upon removal of the patch, any slight reddening of the skin will usually disappear within a few hours. The application site should be changed regularly to prevent local irritation.

Less frequently reported adverse reactions include dizziness, faintness, facial flushing, postural hypotension which may be associated with reflex tachycardia. Syncope, crescendo angina, and rebound hypertension have been reported but are uncommon. Rarely nausea, and vomiting.

8.5 Post-Market Adverse Reactions

The most common adverse drug reaction reported post-market is localized skin reaction (local erythema, pruritus, rash). Other adverse reactions reported rarely in post-marketing use include:

Ophthalmic: blurred vision

Renal: Acute renal failure

Skin: application site pruritus, eczema, rash

Cardiovascular: hypotension, orthostatic hypotension

9 DRUG INTERACTIONS

9.1 Serious Drug Interactions

9.2 Drug Interactions Overview

Concomitant treatment with other vasodilators, calcium channel blockers, angiotensin converting enzyme (ACE) inhibitors, beta-blockers, diuretics, tricyclic antidepressants and major tranquillizers may potentiate the blood pressure lowering effect of TRINIPATCH. Dose adjustment may be necessary.

Concurrent administration of TRINIPATCH with dihydroergotamine may increase the bioavailability of dihydroergotamine.

Use of Acetylsalicylic acid (ASA) and non-steroidal anti-inflammatory drugs (NSAIDS) might diminish the therapeutic response to nitrates and nitroglycerin, and heparin effectiveness may be decreased when used concurrently with nitroglycerin. See 9.4 Drug-Drug Interactions.

9.3 Drug-Behavioural Interactions

Alcohol may enhance sensitivity to the hypotensive effects of nitrates.

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

T=Theoretical

9.5 Drug-Food Interactions

Interactions with food have not been established.

9.6 Drug-Herb Interactions

Interaction with herbal products has not been established.

9.7 Drug-Laboratory Test Interactions

Interaction with laboratory tests has not been established.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

The principal pharmacological action of nitroglycerin is relaxation of vascular smooth muscle, producing a vasodilator effect on both peripheral arteries and veins, with more prominent effects on the latter. Dilation of the post-capillary vessels, including large veins, promotes peripheral pooling of blood and decreases venous return to the heart, thereby reducing left ventricular end-diastolic pressure (preload). Arteriolar relaxation reduces system vascular resistance and arterial pressure (afterload). Dilation of the coronary arteries also occurs. The relative importance of preload reduction, afterload reduction, and coronary dilation remains undefined.

Therapeutic effectiveness depends on its actions on vascular smooth muscle.

Dose-related vasodilation is seen in both the arterial and venous beds, but is most prominent in the latter. The increased venous capacitance (venous pooling) results in a reduction of venous return, ventricular end-diastolic volume, and preload.

In addition, the vasodilating effect on the resistance vessels tends to reduce systolic blood pressure, left ventricular systolic wall tension and afterload. These effects combine to reduce myocardial oxygen requirements.

10.2 Pharmacodynamics

TRINIPATCH transdermal system seems to cause redistribution of coronary blood flow in the endocardium. Nitroglycerin allows the improvement of balance between oxygen supply and demand, while dissipating spontaneously and completely the symptoms of angina pectoris attacks.

The response to nitrate products may differ from patient to patient, while absorption of nitroglycerin resulting from the system may vary between subjects.

Following the application of TRINIPATCH transdermal system onto the skin, constant, continued and prolonged absorption of the active ingredient (nitroglycerin) is initiated, resulting in prolonged venous diastolic action. Onset of action is achieved 30-60 minutes after the application of TRINIPATCH. The duration of action is approximately 24 hours.

10.3 Pharmacokinetics

Absorption

When TRINIPATCH is applied to the skin, nitroglycerin is absorbed directly into the systemic circulation. Thus, the active drug reaches target organs before inactivation by the liver. The transdermal absorption of nitroglycerin occurs in a continuous and well-controlled manner. Bioavailability studies in healthy volunteers have shown that the released amount of nitroglycerin (5 mg or 10mg/24 hours) represents the mean release rate of nitroglycerin resulting from the system and represents the amount available for absorption.

Distribution

The volume of distribution of nitroglycerin is about 3 L/kg, and nitroglycerin is cleared from this volume at extremely rapid rates, with a resulting serum half-life of about 3 minutes. The serum therapeutic level remains undefined. With 50-500 ng/ml plasma concentrations, nitroglycerin is bound to plasma proteins at a rate of approximately 60%, while 1,2 and 1,3-dinitroglycerides are approximately 60% and 30% bound respectively.

The observed clearance rates (close to 1 L/kg/min.) greatly exceed hepatic blood flow, known sites of extrahepatic metabolism include red blood cells and vascular walls.

In healthy volunteers, after the application of TRINIPATCH in different dosages (2 x 7 cm² patch, 1 x 14 cm² patch and 1 x 21 cm² patch), the concentrations of nitroglycerin reached in the plasma were uniform and dose-related, i.e. dependent on drug-release area. They remained constant as long as the system is in contact with the skin (observations have been limited to 24 hours). Upon removal of the patch, the plasma concentrations were maintained for about 30 min. Since the rate of release of nitroglycerin is linearly dependent upon the area of the applied system, two patches of 0.4 mg (or one patch of 0.2 mg and one patch of 0.6 mg) can be used for a dose of 0.8 mg.

Metabolism

Nitroglycerin is rapidly metabolized, principally by a glutathione-dependent organic nitrate reductase in the liver, to form glycerol nitrate metabolites and inorganic nitrate. Two active major metabolites, the 1,2- and 1,3-dinitroglycerols, the products of hydrolysis, appear to be less potent than nitroglycerin as vasodilators but have longer plasma half-lives. The dinitrates are further metabolized to mononitrates (biologically inactive with respect to cardiovascular effects) and ultimately to glycerol and carbon dioxide. There is extensive first-pass deactivation by the liver following gastrointestinal absorption.

Studies with human erythrocytes in-vitro have shown that the erythrocyte is also a site of biotransformation of nitroglycerin by a sulphydryl-dependent enzymatic process and by an interaction with reduced hemoglobin. The amount of reduced hemoglobin in human erythrocytes seems to play a major role in their metabolic activity, and caution should therefore be exercised in cases of anemia. In animal studies it has been found that extrahepatic vascular tissues (femoral vein, inferior vena cava, aorta) likewise play an important role in nitroglycerin metabolism, a finding which is consistent with the large systemic clearance seen with nitrates. It has also been shown in-vitro that the biotransformation of nitroglycerin occurs concurrently with vascular smooth muscle relaxation; this observation is consistent with the hypothesis that nitroglycerin biotransformation is involved in the mechanism of nitroglycerin-induced vasodilation.

Elimination

Metabolic derivatives of nitroglycerin are excreted in the urine.

Special Populations and Conditions

• Pediatrics: No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.
• Geriatrics: No special information is available on the use of TRINIPATCH in geriatric population. However, there is no evidence suggesting that dosage should be adapted in these patients.

11 STORAGE, STABILITY AND DISPOSAL

Storage and stability

Store at controlled room temperature (between 15°C - 30°C).

Each patch is individually sealed in a separate pouch. Do not store out of the pouch. Keep TRINIPATCH out of reach of children and pets before use and when disposing of used patches.

Do not use beyond the expiry date indicated on the label. Do not refrigerate.

Disposal

Each patch can only be applied once. After use, fold the patch in half with the adhesive side inwards. Throw it away safely out of the reach of children and pets.

12 SPECIAL HANDLING INSTRUCTIONS

None required.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Nitroglycerin

Chemical name: 1, 2, 3-propanetriol-trinitrate

Molecular formula and molecular mass: C₃H₅N₃0₉, 227.09

Structural formula:

Physicochemical properties: Freely soluble in ethanol, ether, acetic acid, ethyl acetate and chloroform; soluble in methanol; slightly soluble in water.

14 CLINICAL TRIALS

14.1 Clinical Trials by Indication

Prevention of anginal attacks

The clinical trial data on which the original indication was authorized is not available.

14.2 Comparative Bioavailability Studies

A randomized, two-way crossover study comparing the relative bioavailability of a single-dose application of TRINIPATCH 0.4 mg/hr (44.8 mg/14 cm²) patch against the reference drug product, Transderm Nitropatch 0.4 (50 mg/20 cm²) patch in a total of 30 healthy, non-smoking, male volunteers under fasting conditions.

The rate and extent of absorption of nitroglycerin and its metabolites, 1.2 and 1.3-dinitroglycerin were measured and compared after a single patch application of TRINIPATCH (0.4 mg/hr) and Transderm Nitropatch (0.4 mg/hr).

Table 3 - Comparative bioavailability data

NITROGLYCERIN

1,2 DINITROGLYCERIN

1,3 DINITROGLYCERIN

*These are arithmetic means (CV%)

^$ TRINIPATCH 0.4 (0.4mg/hr)

^& Transderm Nitropatch (0.4 mg/hr).

15 MICROBIOLOGY

No microbiological information is required for this drug product.

16 NON-CLINICAL TOXICOLOGY

General Toxicology:

Acute Toxicity:

The intravenous lethal dose of nitroglycerin was found to be 83.5 mg/kg in the guinea pig, while the intravenous LD50 in rabbits was 43 mg/kg. The lethal dose following intramuscular administration to rabbits, guinea pigs, rats and cats varied between 150 and 500 mg/kg. Orally, doses of 80 to 100 mg/kg were found to be lethal in the guinea pig and rat. Signs and symptoms of toxicity include methemoglobinemia and circulatory collapse leading to convulsions and death.

Subacute Toxicity:

Subcutaneous administration of nitroglycerin at a low dose of 0.1 mg/kg daily to cats for a period of 40 days produced anemia and fatty degeneration of the liver. Daily doses as high as 7.5 or 15 mg/kg given subcutaneously for a period of 50 days were given to cats. Two died after 10 and 20 doses, respectively. The surviving animals showed jaundice and albuminuria, and hemorrhages of the cerebellum, heart, liver and spleen were seen at post-mortem.

Carcinogenicity:

Rats receiving high doses of nitroglycerin in the diet (363 mg/kg/day in males and 434 mg/kg/day in females) for 2 years had an incidence of hepatocellular carcinomas and/or neoplastic nodules of 67% and interstitial cell tumours of the testes of about 50%. Mid-dose rats receiving 31.5 mg/kg/day (males) and 38.1 mg/kg/day (females) had an incidence of hepatocellular carcinomas and/or neoplastic nodules of about 11% versus about 2% in the controls. Mice receiving 1022 mg/kg/day (males) or 1058 mg/kg/day (females) for the same period showed no treatment-related tumours.

Genotoxicity:

There were no apparent nitroglycerin-induced mutagenic effects in the cytogenetics analyses of bone marrow and kidney cells from dogs (up to 25 mg/kg/day in capsules for one year) and rats fed nitroglycerin for 2 years (up to 363 mg/kg/day in males and 434 mg/kg/day in females) and in the dominant lethal mutation study in rats.

Reproductive and Developmental Toxicology:

A three generation reproduction study in rats found adverse effects on fertility in the high dose group (363 and 434 mg/kg/day in the diet for males and females, respectively) resulting from decreased feed intake and consequent poor nutritional status and decreased body weight gain of the females, and decreased spermatogenesis (accompanied by increased interstitial tissue) in the males. Although litter size, birth weight, viability, lactation indices and weaning weight were reduced, there were no specific nitroglycerin-induced teratogenic effects.