LORBRENA Contre-Indications

1 INDICATIONS

LORBRENA (lorlatinib) is indicated as:

• monotherapy for the first-line treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive locally advanced (not amenable to curative therapy) or metastatic non-small cell lung cancer (NSCLC)

• monotherapy for the treatment of adult patients with anaplastic lymphoma kinase (ALK) positive metastatic non-small cell lung cancer (NSCLC) who have progressed on: crizotinib and at least one other ALK inhibitor, or patients who have progressed on ceritinib or alectinib.

  The marketing authorization with conditions was based on a primary efficacy endpoint of tumor objective response rate and duration of response; no overall survival benefit has been demonstrated (see 14 CLINICAL TRIALS).

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): Of the patients in Study B7461001 (N=295) and Study B7461006 (N=149) who received 100 mg LORBRENA orally once daily, 54 (18%) and 59 (40%), respectively, were aged 65 years or older. No clinically important differences in safety or efficacy were observed between patients aged 65 years or older and younger patients (see 10 CLINICAL PHARMACOLOGY).

• LORBRENA (lorlatinib) 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.
• Concomitant use of strong CYP3A inducers with LORBRENA is contraindicated due to the potential for serious hepatoxicity (aspartate aminotransferase [AST] and alanine aminotransferase [ALT] elevations (see 4 DOSAGE AND ADMINISTRATION and 9 DRUG INTERACTIONS).

4.1 Dosing Considerations

• Strong cytochrome P-450 (CYP)3A inhibitors: Concurrent use of LORBRENA (lorlatinib) with strong CYP3A inhibitors may increase lorlatinib plasma concentrations. Concomitant use of LORBRENA with strong CYP3A inhibitors should be avoided.  An alternative concomitant medicinal product with less potential to inhibit CYP3A should be considered (see 9 DRUG INTERACTIONS). If a strong CYP3A inhibitor must be co administered concomitantly, the LORBRENA dose of 100 mg once daily should be reduced to once daily 75 mg dose (see 9 DRUG INTERACTIONS and 10 CLINICAL PHARMACOLOGY).  If concurrent use of a strong CYP3A inhibitor is discontinued, LORBRENA should be resumed at the dose used prior to the initiation of the strong CYP3A inhibitor and after a washout period of 3 to 5 half lives of the CYP3A inhibitor.
• Dosing modification for Fluconazole: Avoid concomitant use of LORBRENA with fluconazole, based on Physiologically-Based Pharmacokinetic (PBPK) simulation. If concomitant use is unavoidable, reduce the starting dose of LORBRENA to 75 mg once daily.
• Strong CYP3A inducers: LORBRENA is contraindicated in patients taking strong CYP3A inducers. Discontinue strong CYP3A inducers for 3 plasma half-lives of the strong CYP3A inducer prior to initiating LORBRENA.
• Moderate CYP3A inducers: Avoid concomitant use with moderate CYP3A inducers as they may reduce lorlatinib plasma concentrations. If concomitant use is unavoidable, increase the starting dose of LORBRENA to 125 mg once daily.
• Hepatic impairment: A formal hepatic impairment study has not been conducted with lorlatinib. No dose adjustments are recommended for patients with mild hepatic impairment. Limited information is available for LORBRENA in patients with moderate or severe hepatic impairment (see 10 CLINICAL PHARMACOLOGY).
• Renal impairment: No dose adjustment is needed for patients with mild or moderate impairment [absolute estimated glomerular filtration rate ≥ 30 mL/min). Reduce the dose when administering LORBRENA in patients with severe renal impairment (absolute eGFR < 30 mL/min) from 100 mg to 75 mg orally once daily (see 10 CLINICAL PHARMACOLOGY). Lorlatinb is not recommended for patients requiring hemodialysis as information for use in these patients is very limited.

4.2 Recommended Dose and Dosage Adjustment

Recommended Dose:

The recommended dose of LORBRENA is 100 mg taken orally once daily continuously. Continue treatment with LORBRENA until disease progression or unacceptable toxicity.

LORBRENA may be taken with or without food (see 10 CLINICAL PHARMACOLOGY).

Pediatric patients (<8 years):

The safety and efficacy of LORBRENA in pediatric patients have not been established. Health Canada has not authorized an indication for pediatric use.

Geriatrics (≥ 65 years):

No clinically important differences in safety or efficacy were observed between patients aged 65 years or older and younger patients (see 10 CLINICAL PHARMACOLOGY). 

Dose Modifications:

Dosing interruption and/or dose reduction may be required based on individual safety and tolerability. Dose reduction levels are summarized below.

• First dose reduction: LORBRENA 75 mg taken orally once daily
• Second dose reduction: LORBRENA 50 mg taken orally once daily

LORBRENA should be permanently discontinued if the patient is unable to tolerate LORBRENA 50 mg taken orally once daily.

Dose modification recommendations for toxicities are provided in Table 1. Dose modification recommendations for patients who develop first-degree, second-degree, or complete atrioventricular (AV) block are provided in Table 2.

4.4 Administration

Patients should be encouraged to take their dose of LORBRENA at approximately the same time each day. Tablets should be swallowed whole (tablets should not be chewed, crushed or split prior to swallowing). No tablet should be ingested if it is broken, cracked, or otherwise not intact.

4.5 Missed Dose

If a dose of LORBRENA is missed, then it should be taken as soon as the patient remembers unless it is less than 4 hours before the next dose, in which case the patient should not take the missed dose. Patients should not take 2 doses at the same time to make up for a missed dose.

There is no known antidote for LORBRENA (lorlatinib). The treatment of LORBRENA overdose should consist of general supportive measures.  Given the dose‑dependent effect on PR interval, ECG monitoring is recommended.

Description

25 mg: 8 mm round tan immediate release film-coated tablet, debossed with “Pfizer” on one side and “25” and “LLN” on the other side.

100 mg: oval (17 x 8.5 mm) lavender immediate release film-coated tablet, debossed with “Pfizer” on one side and “LLN 100” on the other side.

Packaging: LORBRENA is supplied as follows:
25 mg

• high density polyethylene bottles containing 30, 60, or 100 tablets
• aluminum foil blisters with aluminum foil backing containing 120 tablets (12 cards of 10 tablets)

100 mg

• high density polyethylene bottles containing 30, 60, or 100 tablets
• aluminum foil blisters with aluminum foil backing containing 30 tablets (3 cards of 10 tablets)

Please see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX.

General

Patients treated with LORBRENA (lorlatinib) must have a documented ALK-positive status based on a validated ALK assay. Assessment of ALK-positive NSCLC should be performed by laboratories with demonstrated proficiency in the specific technology being utilized.

Drug-Drug Interactions

Risk of Serious Hepatotoxicity with Concomitant Use of Strong CYP3A Inducers

Severe hepatotoxicity occurred in 10 of 12 healthy subjects receiving a single dose of LORBRENA with multiple daily doses of rifampin, a strong CYP3A inducer. Grade 4 alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevations occurred in 6 subjects (50%), Grade 3 ALT or AST elevations occurred in 4 subjects (33%) and Grade 2 ALT or AST elevations occurred in 1 subject (8%). ALT or AST elevations occurred within 3 days and returned to within normal limits after a median of 15 days (7 to 34 days); the median time to recovery was 18 days in subjects with Grade 3 or 4 ALT or AST elevations and 7 days in subjects with Grade 2 ALT or AST elevations.

No clinically meaningful changes in liver function tests were seen in healthy subjects after receiving a combination of lorlatinib with the moderate CYP3A inducer modafinil (see 9 DRUG INTERACTIONS and 10 CLINICAL PHARMACOLOGY).

Carcinogenesis and Mutagenesis

Please see 16 NON-CLINICAL TOXICOLOGY.

Cardiovascular

Atrioventricular (AV) Block

PR interval prolongation and atrioventricular (AV) block events have been reported in patients receiving LORBRENA. In 476 patients who received 100 mg LORBRENA daily in Study B7461001 (n=327) and Study B7461006 (n=149) and who had a baseline electrocardiography (ECG), 9 patients (1.9%) experienced AV block and 1 patient (0.2%) experienced Grade 3 AV block and underwent pacemaker placement (see 10.2 Pharmacodynamics).

For those patients who develop AV block, dose modification may be required (see 4 DOSAGE AND ADMINISTRATION).

Hypertension

Hypertension can occur in patients receiving LORBRENA (see 8 ADVERSE REACTIONS). Hypertension occurred in 62 patients (13%) who received 100 mg LORBRENA once daily in Study B7461001 and Study B7461006, including Grade 3 or 4 in 29 patients (6.1%). The median time to onset of hypertension was 6.4 months (1 day to 2.8 years), and 11 patients (2.3%) temporarily discontinued LORBRENA for hypertension.

Withhold and resume at a reduced dose or permanently discontinue LORBRENA based on severity (see 4 DOSAGE AND ADMINISTRATION).

Driving and Operating Machinery

LORBRENA has moderate influence on the ability to drive and use machines. Caution should be exercised when driving or operating machines as patients may experience central nervous system effects (see 8.2 Clinical Trial Adverse Reactions, Nervous System Disorders).

Endocrine and Metabolism

Hyperlipidemia

The use of LORBRENA has been associated with increases in serum cholesterol and triglycerides (see 8 ADVERSE REACTIONS). Grade 3 or 4 elevations in total cholesterol occurred in 87 patients (18%) and Grade 3 or 4 elevations in triglycerides occurred in 92 patients (19%) of the 476 patients who received 100 mg LORBRENA once daily in Study B7461001 (n=327) and in Study B7461006 (n=149). The median time to onset for both hypercholesterolemia and hypertriglyceridemia was 15 days. The median duration of hypercholesterolemia and hypertriglyceridemia was 451 and 427 days, respectively. No patient was permanently discontinued from treatment with lorlatinib associated with hypercholesterolemia or hypertriglyceridemia. Eighteen (4%) and 33 (7%) patients required temporary discontinuation and 6 (1%) and 13 (3%) patients required dose reduction of LORBRENA for elevations in cholesterol and in triglycerides in Study B7461001 and Study B7461006, respectively. Three hundred ninety‑seven patients (83%) required initiation of lipid-lowering medications, with a median time to onset of start of such medications of 17 days.

Initiation, or increase in the dose, of lipid-lowering agents is recommended (see 4 DOSAGE AND ADMINISTRATION).

Hyperglycemia

Hyperglycemia can occur in patients receiving LORBRENA (see 8 ADVERSE REACTIONS). Hyperglycemia occurred in 44 patients (9.2%) who received 100 mg LORBRENA once daily in Study B7461001 and Study B7461006, including Grade 3 or 4 in 15 patients (3.2%). The median time to onset of hyperglycemia was 4.8 months (1 day to 2.9 years), and 0.8% of patients temporarily discontinued LORBRENA for hyperglycemia.

Withhold and resume at a reduced dose or permanently discontinue LORBRENA based on severity (see 4 DOSAGE AND ADMINISTRATION).

Monitoring and Laboratory Tests

ALK Testing

Patients treated with LORBRENA must have a documented ALK-positive status based on a validated ALK assay. Assessment of ALK-positive NSCLC should be performed by laboratories with demonstrated proficiency in the specific technology being utilized.

Liver Function Tests

No clinically meaningful changes in liver function tests were seen in healthy subjects after receiving a combination of lorlatinib with the moderate CYP3A inducer modafinil (see 9 DRUG INTERACTIONS and 10 CLINICAL PHARMACOLOGY).

Pancreatic enzymes - Lipase and amylase increase

Patients should be monitored for lipase and amylase elevations prior to the start of LORBRENA treatment and periodically thereafter as clinically indicated.

ECG Monitoring

Monitor ECG prior to initiating LORBRENA and monthly thereafter, particularly in patients with predisposing conditions to the occurrence of clinically significant cardiac events (see 7 WARNINGS AND PRECAUTIONS, Cardiovascular; 4 DOSAGE AND ADMINISTRATION).

Hypertension

Control blood pressure prior to initiation of LORBRENA. Monitor blood pressure after 2 weeks and at least monthly thereafter during treatment with LORBRENA. Withhold and resume at a reduced dose or permanently discontinue LORBRENA based on severity (see 7 WARNINGS AND PRECAUTIONS, Hypertension, 4 DOSAGE AND ADMINISTRATION).

Hyperlipidemia

Monitor serum cholesterol and triglycerides before initiating LORBRENA, 2, 4, and 8 weeks, after initiating LORBRENA, and periodically thereafter. Withhold and resume at the same dose for the first occurrence: resume at the same or a reduced dose of LORBRENA for recurrence based on severity (see 7 WARNINGS AND PRECAUTIONS, Endocrine and Metabolism; 4 DOSAGE AND ADMINISTRATION; 8.2 Clinical Trial Adverse Reactions).
 
Hyperglycemia

Assess fasting serum glucose prior to initiation of LORBRENA and monitor periodically thereafter (see 7 WARNINGS AND PRECAUTIONS, Endocrine and Metabolism; 4 DOSAGE AND ADMINISTRATION)

Neurologic

Central Nervous System Effects

Central nervous system (CNS) effects have been observed in patients receiving LORBRENA (see 8.2 Clinical Trial Adverse Reactions). These include seizures, psychotic effects and changes in cognitive function, mood (including suicidal ideation), speech, mental status, and sleep. Overall, CNS effects occurred in 246 (52%) of the 476 patients who received 100 mg LORBRENA once daily in clinical trials (see 8.2 Clinical Trial Adverse Reactions). Cognitive effects occurred in 132 (28%) of the 476 patients; in 14 patients (2.9%) these events were severe (Grade 3 or 4). Mood effects occurred in 102 patients (21%); in 8 patients (1.7%) these events were severe. Speech effects occurred in 50 patients (11%); in 3 patients (0.6%) these events were severe. Psychotic effects occurred in 33 patients (7%); in 3 patients (0.6%) these events were severe. Mental status changes occurred in 6 patients (1.3%); in 5 patients (1.1%) these events were severe. Seizures occurred in 9 patients (1.9%) patients, sometimes in conjunction with other neurologic findings. Sleep effects occurred in 55 patients (12%). The median time to first onset of any CNS effect was 1.4 months (1 day to 3.4 years). Overall, 10 patients (2.1%) required permanent discontinuation of LORBRENA for a CNS effect; 46 patients (10%) required temporary discontinuation and 36 patients (8%) required dose reduction.

Dose modification may be required for those patients who develop CNS effects. Permanent discontinuation of LORBRENA is recommended in patients diagnosed with Grade 4 CNS effects (see 4 DOSAGE AND ADMINISTRATION).

Reproductive Health: Female and Male Potential

Women of childbearing potential should be advised to avoid becoming pregnant while receiving LORBRENA. A highly effective non-hormonal method of contraception is required for female patients during treatment with LORBRENA because lorlatinib can render hormonal contraceptives ineffective (see 9 DRUG INTERACTIONS). If a hormonal method of contraception is unavoidable, then a condom must be used in combination with the hormonal method. Effective contraception must be continued for at least 21 days after completing therapy. 

During treatment with LORBRENA and for at least 97 days after the final dose, advise male patients with female partners of reproductive potential to use effective contraception, including a condom, and advise male patients with pregnant partners to use condoms.

• Fertility

Based on nonclinical safety findings, male and female fertility may be compromised during treatment with LORBRENA (see 16 NON-CLINICAL TOXICOLOGY). It is not known whether LORBRENA affects female fertility. Men should seek advice on effective fertility preservation before treatment.

Respiratory

ILD/Pneumonitis

Severe or life-threatening pulmonary adverse reactions consistent with pneumonitis have occurred with LORBRENA. Pneumonitis occurred in 9 patients (1.9%) who received 100 mg LORBRENA once daily in Study B7461001 (n=327) and in Study B7461006 (n=149), including Grade 3 or 4 pneumonitis in 3  patients (0.6%). Four patients (0.8%) discontinued LORBRENA for ILD/pneumonitis.

Promptly investigate for ILD/pneumonitis in any patient who presents with worsening of respiratory symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, and fever). Immediately withhold LORBRENA in patients with suspected ILD/pneumonitis. Permanently discontinue LORBRENA for treatment-related ILD/pneumonitis of any severity (see 4 DOSAGE AND ADMINISTRATION).

7.1    Special Populations

7.1.1 Pregnant Women

Studies in animals have shown embryo-fetal toxicity (see 16 NON-CLINICAL TOXICOLOGY). There are no data in pregnant women using LORBRENA. LORBRENA may cause fetal harm when administered to a pregnant woman. 

LORBRENA is not recommended during pregnancy or for women of childbearing potential not using contraception.

7.1.2 Breast-feeding

It is not known whether lorlatinib and its metabolites are excreted in human milk. A risk to the newborn child cannot be excluded.

LORBRENA should not be used during breast-feeding. Breast-feeding should be discontinued during treatment with LORBRENA and for 7 days after the last dose.

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

Among patients from Study B7461001 who received 100 mg LORBRENA orally once daily (n=295), 241 patients were < 65 years and 54 patients were ≥65 years. Among patients from Study B7461006 who received 100 mg LORBRENA orally once daily (n=149), 90 patients were < 65 years and 59 patients were ≥65 years. The following adverse events were more frequently reported in patients ≥65 years: cognitive effects, dyspnea, fatigue, arthralgia, diarrhea, anemia, myalgia, vomiting, back pain and rash. The limited data on the safety and efficacy of LORBRENA in patients aged 65 years and older do not suggest that a dose adjustment is required in elderly patients (see 10 CLINICAL PHARMACOLOGY). No clinically relevant differences in safety or efficacy were observed between patients aged greater than or equal to 65 years and younger patients. 

8.1 Adverse Reaction Overview

The pooled safety population described in the 7 WARNINGS AND PRECAUTIONS section reflects exposure to LORBRENA in 476 patients who received 100 mg LORBRENA once daily in Study B7461001 (N=327) and Study B7461006 (N=149). Among 476 patients who received LORBRENA, 75% were exposed for 6 months or longer and 61% were exposed for greater than 1 year. In this pooled safety population, the most frequent adverse reactions in ≥ 20% of 476 patients who received LORBRENA were edema (56%), peripheral neuropathy (44%), weight gain (31%), cognitive effects (28%), fatigue (27%), dyspnea (27%), arthralgia (24%), diarrhea (23%), mood effects (21%), and cough (21%). Temporary discontinuation occurred 245 (51.5%) of patients, dose reduction occurred in 117 (24.6%) of patients, and permanent discontinuation occurred in 44 (9.2%) of patients. The most frequent Grade 3-4 laboratory abnormalities in ≥ 20% of 476 patients who received LORBRENA were hypercholesterolemia (21%) and hypertriglyceridemia (21%).

Previously Untreated ALK-Positive Metastatic Non-small Cell Lung Cancer (Phase 3 Study B7461006)

The safety of LORBRENA was evaluated in 149 patients with ALK-positive non-small cell lung cancer (NSCLC) in randomized, open-label, active-controlled Phase 3 Study B7461006. The median duration of exposure to LORBRENA was 16.7 months (4 days to 34.3 months) and 76% received LORBRENA for at least 12 months. Patient characteristics were: median age of 59 years (47 to 68 years), age ≥65 years (35%), female (59%), White (49%), Asian (44%), and Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (96%).

The most frequent (≥20%) adverse reactions reported in patients treated with LORBRENA were edema, weight gain, peripheral neuropathy, cognitive effects, diarrhea, and dyspnea. Of the worsening laboratory values, the most frequent (≥30%) were hypertriglyceridemia, hypercholesterolemia, increased creatinine, increased gamma glutamyl transferase (GGT), increased AST, hyperglycemia, increased ALT, increased creatine phosphokinase (CPK), hypoalbuminemia, and anemia.

Serious adverse reactions occurred in 51 (34%) of the 149 patients treated with LORBRENA; the most frequently reported serious adverse reactions were pneumonia in 7 patients (4.7%), dyspnea in 4 patients (2.7%), respiratory failure in 4 patients (2.7%), cognitive effects in 3 patients (2.0%), and pyrexia in 3 patients (2.0%).

Fatal adverse reactions occurred in 7 (4.7%) of patients treated with LORBRENA and included pneumonia in 1 patient (0.7%), respiratory failure in 1 patient (0.7%), cardiac failure acute in 1 patient (0.7%), disease progression in 1 patient (0.7%), lung neoplasm malignant in 1 patient (0.7%), pulmonary embolism in 1 patient (0.7%), and death in 1 patient (0.7%).

Permanent discontinuation of LORBRENA due to adverse reactions occurred in 10 (6.7%) patients. The most frequent adverse reactions that led to permanent discontinuation of LORBRENA was cognitive effects in 2 patients (1.3%). Dose interruption was required in 73 (49%) patients treated with LORBRENA. The most frequent adverse reactions that led to dose interruptions of LORBRENA were hypertriglyceridemia in 11 patients (7.4%), edema in 8 patients (5.4%), pneumonia in 7 patients (4.7%), cognitive effects in 6 patients (4.0%), hypercholesterolemia in 5 patients (3.4%), and mood effects in 5 patients (3.4%). At least 1 dose reduction due to adverse reactions was required in 31 (21%) patients. The most frequent adverse reactions that led to dose reductions were edema in 8 patients (5.4%), hypertriglyceridemia in 6 patients (4.0%), and peripheral neuropathy in 5 patients (3.4%).

Previously Treated ALK-Positive Metastatic NSCLC (Phase 1/2 Study B7461001)

The data from B7461001 described below reflect exposure to LORBRENA in 295 adult patients with ALK positive or ROS1 positive metastatic NSCLC who received LORBRENA 100 mg orally once daily in Study B7461001. The majority of subjects (232 subjects, 78.6%) had been previously treated with 1 or more ALK or ROS1 TKIs.

The median duration of treatment was 12.5 months (range: 1 day to 35 months), the median age was 53 years (range: 19 to 85 years), and 18% of patients were older than 65 years. A total of 170 patients (58%) were female, 145 patients (49%) were White, and 108 patients (37%) were Asian.

The most frequent (≥ 20%) adverse reactions were edema, peripheral neuropathy, cognitive effects, dyspnea, fatigue, weight increased, arthralgia, mood effects and diarrhea.

Of the worsening laboratory values occurring in ≥ 20% of patients, the most frequent were hypercholesterolemia, hypertriglyceridemia, anemia, hyperglycemia, increased AST, hypoalbuminemia, increased ALT, lipase increased, and increased alkaline phosphatase.
 
Serious adverse reactions occurred in 95 (32%) of the 295 patients; the most frequently reported serious adverse reactions were pneumonia in 10 patients (3.4%), dyspnea in 8 patients (2.7%), pyrexia in 6 patients (2%), mental status changes in 4 patients (1.4%), and respiratory failure in 4 patients (1.4%). Fatal adverse reactions occurred in 8 patients (2.7%) and included pneumonia in 2 patients (0.7%), myocardial infarction in 2 patients (0.7%), acute pulmonary edema in 1 patient (0.3%), embolism in 1 patient (0.3%), peripheral artery occlusion in 1 patient (0.3%), and respiratory distress in 1 patient (0.3%). Permanent discontinuation of LORBRENA for adverse reactions occurred in 23 patients (8%).

The most frequent adverse reactions that led to permanent discontinuation were respiratory failure in 4 patients (1.4%), dyspnea in 2 patients (0.7%), myocardial infarction in 2 patients (0.7%), cognitive effects in 2 patients (0.7%) and mood effects in 2 patients (0.7%). Dose interruption was required in 142 patients (48%). The most frequent adverse reactions that led to dose interruptions were edema in 20 patients (7%), hypertriglyceridemia in 17 patients (6%), peripheral neuropathy in 15 patients (5%), cognitive effects in 13 patients (4.4%), increased lipase in 11 patients (3.7%), hypercholesterolemia in 10 patients (3.4%), mood effects in 9 patients (3.1%), dyspnea in 8 patients (2.7%), pneumonia in 8 patients (2.7%), and hypertension in 6 patients (2.0%). At least 1 dose reduction due to adverse reactions was required in 71 patients (24%). The most frequent adverse reactions that led to dose reductions were edema in 18 patients (6%), peripheral neuropathy in 14 patients (4.7%), cognitive effects in 12 patients (4.1%), and mood effects in 9 patients (3.1%).

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.

Table 3 summarizes the most frequent adverse reactions in patients treated with LORBRENA in the Phase 3 study.

Table 4 summarizes the most frequent adverse reactions in patients treated with LORBRENA in the Phase 1/2 Study B7461001.

8.2.1 Clinical Trial Adverse Reactions – Pediatrics

Not applicable

8.3 Less Common Clinical Trial Adverse Reactions

In Study B7461006, additional clinically significant adverse reactions occurring at an overall incidence between 1% and 10% in patients treated with LORBRENA included speech effects in 10 patients (6.7%) and psychotic effects in 5 patients (3.4%).

In study B7461001, additional clinically significant adverse reactions occurring at an overall incidence between 1% and 10% in patients treated with LORBRENA included psychotic effects in 21 patients (7%).

8.3.1 Less Common Clinical Trial Adverse Reactions – Pediatrics

Not applicable

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

Clinical Trial Findings

Table 5 summarizes laboratory abnormalities in patients treated with LORBRENA in Phase 3 study B7461006.

 Table 6 summarizes laboratory abnormalities in patients treated with LORBRENA in Phase 1/2 Study B7461001.

8.5 Post-Market Adverse Reactions

Not applicable

9.2 Drug Interactions Overview

In vitro data indicate that LORBRENA (lorlatinib) is primarily metabolized by CYP3A4 and uridine diphosphate-glucuronosyltransferase (UGT) 1A4, with minor contributions from CYP2C8, CYP2C19, CYP3A5, and UGT1A3.

9.4 Drug-Drug Interactions

CYP3A inhibitors

Itraconazole, a strong inhibitor of CYP3A, administered at a dose of 200 mg once daily for 5 days, increased the mean area under the curve (AUC) by 42% and C_max by 24% of a single 100 mg oral dose of lorlatinib in healthy volunteers. Concomitant administration of lorlatinib with strong CYP3A inhibitors (e.g., boceprevir, cobicistat, conivaptan, itraconazole, ketoconazole, posaconazole, telaprevir, troleandomycin, voriconazole, ritonavir, paritaprevir in combination with ritonavir and ombitasvir and/or dasabuvir, and ritonavir in combination with either danoprevir, elvitegravir, indinavir, lopinavir, saquinavir, or tipranavir) may increase lorlatinib plasma concentrations. Grapefruit products may also increase lorlatinib plasma concentrations. Concomitant use with a strong CYP3A inhibitor increased lorlatinib plasma concentrations, which may increase the incidence and severity of adverse reactions of LORBRENA. An alternative concomitant medicinal product with less potential to inhibit CYP3A should be considered.  If a strong CYP3A inhibitor must be concomitantly administered, a dose reduction of lorlatinib is recommended (see 4 DOSAGE AND ADMINISTRATION). Based on PBPK simulations, concomitant use of LORBRENA with fluconazole may increase lorlatinib plasma concentrations, which may increase the incidence and severity of adverse reactions of LORBRENA. Avoid concomitant use of LORBRENA with fluconazole. If concomitant use cannot be avoided, reduce the LORBRENA starting dose to 75 mg once daily.

CYP3A inducers

Rifampin, a strong inducer of CYP3A, administered at a dose of 600 mg once daily for 9 days, reduced the mean lorlatinib AUC by 85% and C_max by 76% of a single 100-mg dose of lorlatinib in healthy volunteers; increases in liver function tests (AST and ALT) were also observed. Concomitant administration of lorlatinib with strong CYP3A inducers (e.g., rifampin, carbamazepine, enzalutamide, mitotane, phenytoin and St. John’s wort) may decrease lorlatinib plasma concentrations. Severe hepatotoxicity occurred in healthy subjects receiving LORBRENA with rifampin, a strong CYP3A inducer. The use of a strong CYP3A inducer with lorlatinib is contraindicated (see 2 CONTRAINDICATIONS and 4 DOSAGE AND ADMINISTRATION). Any strong CYP3A inducers have to be discontinued for at least 3 plasma half-lives of the strong CYP3A inducer before lorlatinib treatment is started.  No clinically meaningful changes in liver function test results were seen after administration of the combination of a single 100 mg oral dose of lorlatinib with the moderate CYP3A inducer, modafinil (400 mg once daily for 19 days) in healthy volunteers. Concomitant use of lorlatinib with a moderate CYP3A inducer decreased lorlatinib plasma AUC by 23% and decreased C_max by 22%.  (see 10 CLINICAL PHARMACOLOGY). If concomitant use cannot be avoided, increase LORBRENA starting dose to 125 mg once daily.

Proton Pump inhibitors, H2-receptor antagonists, or locally acting antacids

The proton-pump inhibitor rabeprazole had a minimal effect on lorlatinib plasma exposure (90% CI for the AUC_inf ratio, expressed as a percentage: 97.6%, 104.3%).

No dose adjustment is required when lorlatinib is taken with proton-pump inhibitors, H2-receptor antagonists, or locally acting antacids.

Drugs whose plasma concentrations may be altered by lorlatinib:

CYP3A substrates

Lorlatinib has a net induction effect on CYP3A both in vitro and in vivo. Lorlatinib 150 mg orally once daily for 15 days decreased AUC_inf by 64% and C_max by 50% of a single oral 2 mg dose of midazolam (a sensitive CYP3A substrate). Concurrent administration of lorlatinib in patients resulted in decreased mean oral midazolam AUC and C_max than that observed when midazolam was administered alone, suggesting that lorlatinib is an inducer of CYP3A. Thus, coadministration of lorlatinib with CYP3A substrates with narrow therapeutic indices, including but not limited to hormonal contraceptives, alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus, should be avoided since the concentration of these drugs may be reduced by lorlatinib.

In vitro studies of other CYP inhibition and induction

In vitro studies indicated that clinical drug-drug interactions as a result of lorlatinib mediated inhibition of the metabolism of substrates for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 are unlikely to occur.

In vitro, studies indicated that lorlatinib is an inhibitor of CYP2C9 and that it activates the human pregnane X receptor (PXR), with the net effect in vivo being weak CYP2C9 induction. In vitro studies also indicated that lorlatinib is a time-dependent inhibitor as well as an inducer of CYP3A, with the net effect in vivo being induction.  In vitro studies also indicated that lorlatinib is an inducer of CYP2B6 and activates the human constitutive androstane receptor (CAR), and in vivo lorlatinib is a weak inducer of CYP2B6.  Therefore, concomitant use of lorlatinib with CYP2B6 substrates (e.g., bupropion, efavirenz) may result in reduced plasma concentrations of the CYP2B6 substrate. In vitro, lorlatinib has a low potential to cause drug-drug interactions by induction of CYP1A2.

In vitro, the major circulating metabolite for lorlatinib showed a low potential to cause drug‑drug interaction by inhibiting CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A, or by inducing CYP1A2, CYP2B6, and CYP3A.

In vitro studies of UDP-glucuronysyltransferase (UGT) inhibition

In vitro studies indicated that clinical drug-drug interactions as a result of lorlatinib mediated inhibition of the metabolism of substrates for UGT1A1, UGT1A4, UGT1A6, UGT1A9, UGT2B7 and UGT2B15 are unlikely to occur.  In vitro studies indicated that lorlatinib is an inhibitor of UGT1A1 and that it activates PXR, with the net effect in vivo being weak UGT induction.

In vitro studies indicated that clinical drug‑drug interactions as a result of inhibition by the major lorlatinib circulating metabolite of substrates for UGT1A1, UGT1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B15 are unlikely to occur.

In vitro studies with drug transporters

In vitro studies indicated that clinical drug-drug interactions as a result of lorlatinib mediated inhibition of breast cancer resistance protein (BCRP, systemically), organic anion transporting polypeptide (OATP)1B1, OATP1B3, multidrug and toxin extrusion protein (MATE)2K, organic anion transporter (OAT)1, and organic cation transporter (OCT)2 are unlikely. In vitro studies indicated that lorlatinib is an inhibitor of P-glycoprotein (P-gp) and that it activates PXR, with the net effect in vivo being moderate P‑gp induction.  Lorlatinib may have the potential to inhibit P glycoprotein (P-gp, systemically and at the gastrointestinal [GI] tract), BCRP (GI tract), OCT1, MATE1, and OAT3 at clinically relevant concentrations.

In vitro studies indicated that clinical drug-drug interactions as a result of inhibition by the major lorlatinib circulating metabolite of substrates for P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, and MATE2K are unlikely to occur.

In vivo studies with drug transporters

A drug interaction study conducted in non-small cell lung cancer patients indicated that lorlatinib is a moderate inducer of P gp. P-gp substrates with narrow therapeutic index (e.g., digoxin) should be used with caution in combination with lorlatinib due to the likelihood of reduced plasma concentrations of these substrates.

9.5 Drug-Food Interactions

Lorlatinib can be taken with or without food. Administration of lorlatinib with a high fat, high calorie meal resulted in 5% higher AUC_inf and 9% lower C_max (AUC_inf ratio of 104.7%; 90% CI for the ratio: 101.3%, 108.3%; C_max ratio of 90.89%; 90% CI for the ratio: 84.82%, 97.40%), compared to overnight fasting. However, taking lorlatinib with foods that are strong CYP3A inhibitors (e.g. Grapefruit products) may increase lorlatinib plasma concentrations and should be avoided.

9.6 Drug-Herb Interactions

Co-administration of lorlatinib with herbal products that are strong CYP3A inducers (e.g. St. John’s wort) may decrease lorlatinib plasma concentrations. The use of a strong CYP3A inducer with lorlatinib is contraindicated (see 2 CONTRAINDICATIONS and 4 DOSAGE AND ADMINISTRATION). Avoid concomitant use with herbal products that are moderate CYP3A inducers, if possible, as they may also reduce lorlatinib plasma concentrations.

10.1 Mechanism of Action

Lorlatinib is a selective, adenosine triphosphate (ATP) competitive, brain-penetrant, small molecule inhibitor of ALK and ROS1 tyrosine kinases that addresses mechanisms of resistance following previous treatment with ALK inhibitor therapy.

10.2 Pharmacodynamics

In nonclinical studies, lorlatinib potently inhibited catalytic activities of non‑mutated ALK and a broad range of clinically relevant ALK mutant kinases in recombinant enzyme and cell-based assays. The ALK mutations analyzed included those conferring resistance to other ALK inhibitors.

Lorlatinib demonstrated marked antitumor activity at low nanomolar free plasma concentrations in mice bearing tumor xenografts that express echinoderm microtubule‑associated protein‑like 4 (EML4) fusions with ALK variant 1 (v1), including ALK mutations L1196M, G1269A, G1202R, and I1171T. Two of these ALK mutants, G1202R and I1171T, are known to confer resistance to first and second generation ALK inhibitors. Lorlatinib is also capable of penetrating the blood‑brain barrier and achieved efficacious brain exposure in mice and rat. In mice bearing orthotropic EML4‑ALK or EML4‑ALK^L1196M brain tumor implants, lorlatinib caused tumor shrinkage and prolonged survival. The overall antitumor efficacy of lorlatinib was dose-dependent and correlated with inhibition of ALK phosphorylation.

Cardiac electrophysiology

QT interval

In B7461001, 2 patients (0.7%) had absolute Fridericia’s correction QTc (QTcF) values >500 msec, and 5 patients (1.8%) had a change in QTcF from baseline >60 msec.

In addition, the effect of a single oral dose of lorlatinib (50 mg, 75 mg, and 100 mg) with and without 200 mg once daily itraconazole was evaluated in a 2-way crossover study in 16 healthy volunteers. No increases in the mean QTc interval were observed at the mean observed lorlatinib concentrations in this study.

PR interval

In 295 patients who received lorlatinib at the recommended dose of 100 mg once daily and had a ECG measurement in Study B7461001, the maximum mean change from baseline for PR interval was 16.4 ms (90% CI: 13.4, 19.4 ms). Among the 284 patients with PR interval <200 ms, 14% (40 patients) had PR interval prolongation ≥200 ms after starting lorlatinib. The prolongation of PR interval occurred in a concentration dependent manner. Atrioventricular block occurred in 1.0% of patients.
 
For those patients who develop PR prolongation, dose modification may be required (see 4 DOSAGE AND ADMINISTRATION).

10.3 Pharmacokinetics

Absorption

In patients with cancer, peak lorlatinib concentrations in plasma are rapidly reached with the median T_max of 1.2hours following a single 100 mg dose and 2.0 hours following 100 mg once daily multiple dosing.

After oral administration of lorlatinib tablets, the mean absolute bioavailability is 80.8% (90% CI: 75.7%, 86.2%) compared to intravenous administration.

Administration of lorlatinib with a high fat, high calorie meal resulted in 5% higher AUC_inf and 9% lower C_max (AUC_inf ratio of 104.7%; 90% CI for the ratio: 101.3%, 108.3%; C_max ratio of 90.89%; 90% CI for the ratio: 84.82%, 97.40%), compared to overnight fasting. Lorlatinib may be administered with or without food. The proton pump inhibitor rabeprazole had a minimal effect on lorlatinib plasma exposure (AUC_inf ratio of 100.9%; 90% CI for the ratio: 97.6%, 104.3%). No dose adjustment is recommended when lorlatinib is taken with proton pump inhibitors, H2 receptor antagonists or locally acting antacids.

After multiple QD dose administration, lorlatinib C_max increased dose-proportionally and AUCtau increased slightly less than dose-proportionally over the dose range of 10 mg to 200 mg QD.

At the 100 mg once daily lorlatinib dose, the Cycle 1 Day 15 geometric mean (geometric %CV) peak plasma concentration was 577 (42 ng/mL and the AUC24 5650 (39) ng·h/mL in patients with cancer. The geometric mean (geometric %CV) oral clearance was 17.7 (39) L/h.

Distribution:

In vitro binding of lorlatinib to human plasma proteins is 66% with moderate binding to both albumin and α1-acid glycoprotein.

The geometric mean (geometric %CV) steady state volume of distribution (Vss) of lorlatinib was 305 (28) L following 50 mg IV administration to healthy subjects. In patients with cancer, the geometric mean (geometric %CV) Vz/F after 100 mg single dose was 352 (37) L.

Metabolism:

In humans, lorlatinib undergoes oxidation and glucuronidation as the primary metabolic pathways. In vitro data indicate that lorlatinib is metabolized primarily by CYP3A4 and UGT1A4, with minor contribution from CYP2C8, CYP2C19, CYP3A5, and UGT1A3.

In plasma, a benzoic acid metabolite of lorlatinib resulting from the oxidative cleavage of the amide and aromatic ether bonds of lorlatinib was observed as a major metabolite, accounting for 21% of the circulating radioactivity. The oxidative cleavage metabolite is pharmacologically inactive.

Elimination:

In patients with cancer, the plasma half life of lorlatinib after a single 100 mg dose was 23.6 hours. At steady state, lorlatinib plasma exposures are lower than those expected from single dose pharmacokinetics, indicating a net auto induction effect on lorlatinib metabolism. Following oral administration of a 100 mg radiolabeled dose of lorlatinib, a mean 47.7% of the radioactivity was recovered in urine and 40.9% of the radioactivity was recovered in feces, with overall mean total recovery of 88.6%.

Unchanged lorlatinib was the major component of human plasma and feces, accounting for 44% and 9.1% of total radioactivity in plasma and feces, respectively. Less than 1% of unchanged lorlatinib was detected in urine.

Special Populations and Conditions

• Pediatrics The safety and efficacy of LORBRENA (lorlatinib) in pediatric patients have not been established.
• Geriatrics Out of the 476 patients who received lorlatinib 100 mg orally once daily in B7461001 (N=327) and Study B7461006 (N=149), 25.5% of patients were aged 65 years or older. Of the 215 patients in the efficacy population in Study B7461001, 17.7% of patients were aged 65 years or older, and of the 149 patients in the lorlatinib arm of Study B7461006, 40% were aged 65 years or older. No clinically relevant differences in safety or efficacy were observed between patients aged greater than or equal to 65 years of age and younger patients (see 4 DOSAGE AND ADMINISTRATION).
• Age, gender, race, body weight, and phenotype: Population pharmacokinetic analyses in patients with advanced NSCLC and healthy volunteers indicate that there are no clinically relevant effects of age, gender, race, body weight, or phenotypes for CYP3A5 and CYP2C19.
• Hepatic Insufficiency As lorlatinib is metabolized in the liver, hepatic impairment is likely to increase lorlatinib plasma concentrations. Clinical studies that were conducted excluded patients with AST or ALT >2.5 × ULN, or if due to underlying malignancy, >5.0 × ULN or with total bilirubin >1.5 × ULN. Population pharmacokinetic analyses have shown that lorlatinib exposure was not clinically meaningfully altered in patients with mild hepatic impairment (n=50). No dose adjustments are recommended for patients with mild hepatic impairment (see 4 DOSAGE AND ADMINISTRATION). LORBRENA has not been studied in patients with moderate or severe hepatic impairment.
• Renal Insufficiency Less than 1% of the administered dose is detected unchanged lorlatinib in urine. Clinical studies excluded patients with serum creatinine >1.5 × ULN or estimated CL_cr <60 mL/min. Population pharmacokinetic analyses have shown that lorlatinib steady state exposure was not clinically meaningfully altered in patients with mild (n=103, CL _cr: 60-89 mL/min) or moderate renal impairment (n=41, CL _cr: 30-59 mL/min). Based on a renal impairment study, no dose adjustments are recommended for patients with mild or moderate renal impairment [absolute eGFR based on Modification of Diet in Renal Disease Study equation (MDRD)-derived eGFR (in mL/min/1.73 m2) × measured body surface area/1.73 ≥30 mL/min]. In this study, lorlatinib AUC_inf increased by 41% in subjects with severe renal impairment (absolute eGFR<30 mL/min) compared to subjects with normal renal function (absolute eGFR≥90 mL/min). -Reduce the recommended dosage of LORBRENA in patients with severe renal impairment, from 100 mg to 75 mg orally once daily (see 4 DOSAGE AND ADMINISTRATION).

Store at 15°C to 30°C in the original package to protect from light.

LORBRENA does not require any special handling instructions.

Control #: 248101
November 8, 2021

ACCURETIC (quinapril hydrochloride and hydrochlorothiazide) is indicated for the treatment of essential hypertension in patients for whom combination therapy is appropriate.

ACCURETIC is not indicated for initial therapy. Patients in whom quinapril and hydrochlorothiazide are initiated simultaneously can develop symptomatic hypotension (see WARNINGS AND PRECAUTIONS, Cardiovascular, - Hypotension and DRUG INTERACTIONS).

Patients should be titrated on the individual drugs. If the fixed combination represents the dosage determined by this titration, the use of ACCURETIC may be more convenient in the management of patients. If during maintenance therapy dosage adjustment is necessary, it is advisable to use individual drugs.

Pediatrics (<18 years of age)

The safety and effectiveness of ACCUPRIL in children have not been established, therefore use in this age group is not recommended.

General

Head and Neck Angioedema

Head and neck angioedema has been reported in patients treated with ACCUPRIL. Angioedema associated with laryngeal involvement may be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, ACCUPRIL should be discontinued immediately, the patient treated appropriately in accordance with accepted medical care, and carefully observed until the swelling disappears. In instances where swelling is confined to the face and lips, the condition generally resolves without treatment, although antihistamines may be useful in relieving symptoms. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy (including but not limited to 0.3 to 0.5 mL of subcutaneous epinephrine solution 1:1000) should be administered promptly (see ADVERSE REACTIONS).

The incidence of angioedema during ACE inhibitor therapy has been reported to be higher in black than in non-black patients.

Patients taking concomitant mTOR inhibitor (e.g. temsirolimus) or concomitant DPP-IV inhibitor (e.g. sitagliptin) therapy may be at increased risk for angioedema. Caution should be used when either initiating ACE inhibitor therapy in patients already taking an mTOR or DPP-IV inhibitor or vice versa (see DRUG INTERACTIONS).

Patients with a history of angioedema related or unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see CONTRAINDICATIONS).

Intestinal Angioedema

Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.

Cardiovascular

Dual blockade of the Renin-Angiotensin System (RAS)

Dual blockade of the Renin-Angiotensin System (RAS): There is evidence that co-administration of angiotensin converting enzyme (ACE) inhibitors, such as ACCUPRIL, or of angiotensin receptor antagonists (ARBs) with aliskiren increases the risk of hypotension, syncope, stroke, hyperkalemia and deterioration of renal function, including acute renal failure, in patients with diabetes mellitus (type 1 or type 2) and/or moderate to severe kidney insufficiency (GFR < 60 mL/min/1.73 m²). Therefore, the use of ACCUPRIL in combination with aliskiren-containing drugs is contraindicated in these patients (see CONTRAINDICATIONS).

Further, co-administration of ACE inhibitors, including ACCUPRIL, with other agents blocking the RAS, such as ARBs or aliskiren-containing drugs, is generally not recommended in other patients, since such treatment has been associated with an increased incidence of severe hypotension, renal failure, and hyperkalemia. Administration should be limited to individually defined cases with close monitoring of renal function and blood potassium levels (see CONTRAINDICATIONS).

Hypotension

Symptomatic hypotension has occurred after administration of ACCUPRIL, usually after the first or second dose or when the dose was increased. It is more likely to occur in patients who are volume depleted by diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. In patients with ischemic heart or cerebrovascular disease, an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident (See ADVERSE REACTIONS). Because of the potential fall in blood pressure in these patients, therapy with ACCUPRIL should be started under close medical supervision (see DOSAGE AND ADMINISTRATION). Such patients should be followed closely for the first weeks of treatment and whenever the dose of ACCUPRIL is increased. In patients with severe congestive heart failure, with or without associated renal insufficiency, excessive hypotension has been observed and may be associated with oliguria and/or progressive azotemia, and rarely with acute failure and/or death.

If hypotension occurs, the patient should be placed in supine position and, if necessary, receive an intravenous infusion of 0.9% sodium chloride. A transient hypotensive response is not a contraindication to further doses which usually can be given without difficulty once the blood pressure has increased after volume expansion. However, lower doses of ACCUPRIL and/or reduced concomitant diuretic therapy should be considered.

Valvular Stenosis

There is concern on theoretical grounds that patients with aortic stenosis might be at particular risk of decreased coronary perfusion when treated with vasodilators because they do not develop as much afterload reduction.

Endocrine and Metabolism

Hyperkalemia and Potassium-Sparing Diuretics

Elevated serum potassium (>5.7 mMol/L) was observed in approximately 2% of patients receiving ACCUPRIL. In most cases these were isolated values which resolved despite continued therapy. Hyperkalemia was a cause of discontinuation of therapy in <0.1% of hypertensive patients. Risk factors for the development of hyperkalemia may include renal insufficiency, diabetes mellitus, and the concomitant use of agents to treat hypokalemia (see WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Test, Hyperkalemia, ADVERSE REACTIONS and DRUG INTERACTIONS, Agents Increasing Serum Potassium).

Hypoglycemia and Diabetes

ACE inhibitors may reduce insulin resistance and may lead to hypoglycemia in diabetic patients on insulin or oral hypoglycemic agents; closer monitoring of diabetic patients may be required.

Hematologic

Neutropenia/Agranulocytosis

Agranulocytosis and bone marrow depression have been caused by ACE inhibitors. Agranulocytosis did occur during ACCUPRIL treatment in 1 patient with a history of neutropenia during previous captopril therapy. Periodic monitoring of white blood cell counts should be considered, especially in patients with collagen vascular disease and/or renal disease.

Hepatic

Patients with Impaired Liver Function

Hepatitis (hepatocellular and/or cholestatic), elevations of liver enzymes and/or serum bilirubin have occurred during therapy with other ACE inhibitors in patients with or without pre-existing liver abnormalities. In most cases the changes were reversed on discontinuation of the drug.

Elevations of liver enzymes and/or serum bilirubin have been reported for ACCUPRIL (see ADVERSE REACTIONS). Should the patient receiving ACCUPRIL experience any unexplained symptoms particularly during the first weeks or months of treatment, it is recommended that a full set of liver function tests and any other necessary investigation be carried out. Discontinuation of ACCUPRIL should be considered when appropriate.

There are no adequate studies in patients with cirrhosis and/or liver dysfunction. ACCUPRIL should be used with particular caution in patients with pre-existing liver abnormalities. In such patients baseline liver function tests should be obtained before administration of the drug and close monitoring of response and metabolic effects should apply.

ACCUPRIL (quinapril), when combined with a diuretic should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma. The metabolism of quinapril to quinaprilat is normally dependent upon hepatic esterase. Quinaprilat concentrations are reduced in patients with alcoholic cirrhosis due to impaired deesterification of quinapril.

Immune

Anaphylactoid Reactions during Membrane Exposure

Anaphylactoid reactions have been reported in patients dialysed with high-flux membranes (e.g.: polyacrylonitrile [PAN]) and treated concomitantly with an ACE inhibitor. Dialysis should be stopped immediately if symptoms such as nausea, abdominal cramps, burning, angioedema, shortness of breath and severe hypotension occur. Symptoms are not relieved by antihistamines. In these patients consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agents.

Anaphylactoid Reactions during LDL Apheresis

Rarely, patients receiving ACE inhibitors during low density lipoprotein apheresis with dextran sulfate have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding the ACE inhibitor therapy prior to each apheresis.

Anaphylactoid Reactions during Desensitization

There have been isolated reports of patients experiencing sustained life threatening anaphylactoid reactions while receiving ACE inhibitors during desensitizing treatment with hymenoptera (bees, wasps) venom. In the same patients, these reactions have been avoided when ACE inhibitors were temporarily withheld for at least 24 hours, but they have reappeared upon inadvertent rechallenge to an ACE inhibitor.

Nitritoid Reactions-Gold

Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and symptomatic hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including ACCUPRIL (see DRUG INTERACTIONS).

Neurologic

Driving and Operating Machinery

The ability to engage in activities such as operating machinery or operating a motor vehicle may be impaired, especially when initiating quinapril therapy.

Peri-Operative Considerations

Surgery/Anaesthesia

In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, ACCUPRIL will block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.

Renal

Renal Impairment

The use of ACE inhibitors, including ACCUPRIL, with ARBs or aliskiren-containing drugs is contraindicated in patients with moderate to severe kidney insufficiency (GFR < 60 mL/min/1.73m²) (see CONTRAINDICATIONS and DRUG INTERACTIONS, Aliskiren- containing medicines and Angiotensin receptor blockers (ARBs) or other ACE inhibitors).

As a consequence of inhibiting the renin-angiotensin-aldosterone system (RAAS), changes in renal function have been seen in susceptible individuals. In patients whose renal function may depend on the activity of the RAAS, such as patients with bilateral renal artery stenosis, unilateral renal artery stenosis to a solitary kidney, or severe congestive heart failure, treatment with agents that inhibit this system has been associated with oliguria, progressive azotemia, and rarely, acute renal failure and/or death. In susceptible patients, concomitant diuretic use may further increase risk (see ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION). Use of ACCUPRIL should include appropriate assessment of renal function (see ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION).

Respiratory

Cough

Cough has been reported with the use of ACE inhibitors, including quinapril. Characteristically, the cough is dry and persistent and usually disappears only after withdrawal or lowering of the dose of ACCUPRIL. ACE inhibitor-induced cough should be considered as part of the differential diagnosis of the cough.

Sensitivity/Resistance

Due to the presence of lactose, patients with hereditary problems of galactose intolerance, glucose-galactose malabsorption or the Lapp lactase deficiency should not take ACCUPRIL (see CONTRAINDICATIONS).

Special Populations

Pregnant Women

Quinapril is contraindicated in pregnancy (see CONTRAINDICATIONS and ADVERSE REACTIONS). ACE inhibitors can cause fetal and neonatal morbidity and mortality when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, ACCUPRIL should be discontinued as soon as possible.

The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development.

Prematurity, and patent ductus arteriosus and other structural cardiac malformations, as well as neurologic malformations have also been reported, following exposure in the first trimester of pregnancy.

Infants with a history of in utero exposure to ACE inhibitors should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as a means of reversing hypotension and/or substituting for impaired renal function, however; limited experience with those procedures has not been associated with significant clinical benefit.

If oligohydramnios is observed, a non-stress test (NST), and/or a biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. If concerns regarding fetal well- being still persist, a contraction stress testing (CST) should be considered. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Animal Data: No fetotoxic or teratogenic effects were observed in rats at doses as high as 300 mg/kg/day (180x the maximum daily human dose), despite maternal toxicity at 150 mg/kg/day. Offspring body weights were reduced in rats treated late in gestation and during lactation with doses of ≥25 mg/kg/day. Quinapril hydrochloride was not teratogenic in rabbits; however, maternal and embryo toxicity were seen in some rabbits at 1 mg/kg/day.

No adverse effects on fertility or reproduction were observed in rats at dose levels ≤100 mg/kg/day (60x the maximum daily human dose) (see TOXICOLOGY, Table 4).

Nursing Women

The presence of concentrations of ACE inhibitor has been reported in human milk. The use of ACCUPRIL is contraindicated during breast-feeding (see CONTRAINDICATIONS).

Pediatrics (<18 years of age)

The safety and effectiveness of ACCUPRIL in children have not been established, therefore use in this age group is not recommended.

Geriatrics (>65 years of age)

Of the total number of subjects in clinical studies of ACCUPRIL, 21% were ≥65 years old. (There was no distinction between patients >65 or >75 years.) No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION).

Elderly patients exhibited increased area under the plasma concentration time curve and peak levels for quinaprilat compared to values observed in younger patients; this appeared to relate to decreased renal function rather than to age itself.

Monitoring and Laboratory Tests

Hematology: Periodic monitoring of white blood cell counts should be considered, especially in patients with collagen vascular disease and/or renal disease (see WARNINGS AND PRECAUTIONS, Hematologic, Neutropenic/Agranulocytisis).
Hyperkalemia: Patients with renal insufficiency, diabetes mellitus or concomitantly taking agents to treat hypokalemia may be at increased risk of developing hyperkalemia. Serum potassium should be monitored regularly (see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, Endocrine and Metabolism, Hyperkalemia and Potassium-Sparing Diuretics).
Creatinine and Blood Urea Nitrogen: Increases (>1.25x the upper limit of normal) in serum creatinine and blood urea nitrogen (BUN) were observed in 2% each of patients treated with ACCUPRIL alone. Increases were more likely to occur in patients receiving concomitant diuretic therapy than in those on ACCUPRIL alone (see WARNINGS AND PRECAUTIONS, Renal, Renal Impairment). These increases often reversed on continued therapy. In controlled studies of heart failure, increases in BUN and serum creatinine were observed in 11% and 8%, respectively, of patients treated with ACCUPRIL. Most often, these patients were receiving diuretics with or without digitalis. Use of ACCUPRIL should include appropriate assessment of renal function.
Hepatic: Elevations of liver enzymes and/or serum bilirubin have occurred in patients receiving ACCUPRIL. If a patient receiving ACCUPRIL experience any unexplained symptoms, particularly during the first weeks or months of treatment, a full set of liver function tests and any other investigation should be carried out. Discontinuation of ACCUPRIL should be considered when appropriate. In patients with pre-existing liver abnormalities, baseline liver function tests should be obtained before administration of the drug and response and metabolic effects should be closely monitored (see WARNINGS AND PRECAUTIONS, Hepatic, Patients with Impaired Liver Function).

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

ACCURETIC (quinapril hydrochloride and hydrochlorothiazide) was evaluated for safety in 1571 patients with essential hypertension, including 943 patients in controlled studies (see Table 1), 345 patients in placebo-controlled trials, and 517 patients who were treated with ACCURETIC for ≥1 year. Adverse reactions were limited to those reported previously with quinapril or hydrochlorothiazide (HCTZ) when used separately for the treatment of hypertension.

Serious or clinically significant adverse reactions observed in <0.2% of patients treated with quinapril and HCTZ were: hematemesis, gout, syncope and angioedema. Therapy was discontinued in 2.1% of patients due to an adverse event (AE). Headache (0.5%) and dizziness (0.3%) were the most frequent reasons for withdrawal.

The most frequent adverse experiences in controlled trials were headache (6.7%), dizziness (4.8%), cough (3.2%) and fatigue (2.9%). The cough is characteristically non- productive, persistent and resolves after discontinuation of therapy (see WARNINGS AND PRECAUTIONS, Respiratory, Cough).

Clinical AEs regardless of relationship to therapy, occurring in ≥0.5% to <1.0% of patients treated with quinapril plus HCTZ in controlled and uncontrolled trials and less frequent clinically significant events seen in clinical trials or in post marketing experience included:

Rare AEs, not listed above, which have been reported with either HCTZ, quinapril, or the combination include:

Drug-Drug Interactions

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

Drug-Food Interactions

The rate and extent of quinapril absorption are diminished moderately (approximately 25-30%) when ACCUPRIL tablets are administered during a high-fat meal. However, no effect on quinapril absorption occurs when taken during a regular meal.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Test Interactions

Interactions with laboratory products/methods have not been established.

Drug-Lifestyle Interactions

Lifestyle interactions have not been established.

Dosage of ACCUPRIL (quinapril hydrochloride) must be individualized.

Hypertension

Initiation of therapy requires consideration of recent antihypertensive drug treatment, the extent of blood pressure (BP) elevation and salt restriction. The dosage of other antihypertensive agents being used with ACCUPRIL may need to be adjusted.

Monotherapy:
The recommended initial dose of ACCUPRIL in patients not on diuretics is 10 mg once daily. An initial dose of 20 mg once daily can be considered for patients without advanced age, renal impairment, or concomitant heart failure and who are not volume depleted (see WARNINGS AND PRECAUTIONS, Cardiovascular, Hypotension). Dosage should be adjusted according to BP response, generally at intervals of 2-4 weeks. A dose of 40 mg daily should not be exceeded.

In some patients treated once daily, the antihypertensive effect may diminish towards the end of the dosing interval. This can be evaluated by measuring BP just prior to dosing to determine whether satisfactory control is being maintained for 24 hours. If it is not, either 2x daily administration with the same total daily dose, or an increase in dose should be considered. If BP is not controlled with ACCUPRIL alone, a diuretic may be added. After the addition of a diuretic, it may be possible to reduce the dose of ACCUPRIL.

Concomitant Diuretic Therapy: Symptomatic hypotension occasionally may occur following the initial dose of ACCUPRIL and is more likely in patients who are currently being treated with a diuretic. The diuretic should, if possible, be discontinued for 2-3 days before beginning therapy with ACCUPRIL to reduce the likelihood of hypotension (See WARNINGS AND PRECAUTIONS, Cardiovascular, Hypotension). If the diuretic cannot be discontinued, an initial dose of 5 mg ACCUPRIL should be used with careful medical supervision for several hours and until BP has stabilized. The dosage of ACCUPRIL should subsequently be titrated (as described above) to the optimal response.

Dosing Adjustment in Renal Impairment: For use in hemodialysis patients, see WARNINGS and PRECAUTIONS, Anaphylactoid Reactions during Membrane Exposure. Quinapril should be administered on days when dialysis is not performed. Starting doses should be reduced according to the following guidelines:

Patients should subsequently have dosage titrated (as described above) to the optimal response.

Dosage in the Elderly (>65 years): The recommended initial dosage of ACCUPRIL is 10 mg once daily (depending on renal function), followed by titration (as described above) to the optimal response.

Congestive Heart Failure

ACCUPRIL is indicated as adjunctive therapy to diuretics, and/or cardiac glycosides. Therapy should be initiated under close medical supervision. BP and renal function should be monitored, both before and during treatment with ACCUPRIL, because severe hypotension and, more rarely, consequent renal failure have been reported (see WARNINGS AND PRECAUTIONS, Cardiovascular, Hypotension).

Initiation of therapy requires consideration of recent diuretic therapy and the possibility of severe salt/volume depletion. If possible, the dose of diuretic should be reduced before beginning treatment, to reduce the likelihood of hypotension. Serum potassium should also be monitored (see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS).

The recommended starting dose is 5 mg once daily, to be administered under close medical supervision to determine the initial effect on BP. After the initial dose, the patient should be observed for ≥2 hours, or until the pressure has stabilized for ≥1 additional hour (See WARNINGS AND PRECAUTIONS, Cardiovascular, Hypotension). This dose may improve symptoms of heart failure, but increases in exercise duration have generally required higher doses. Therefore, if the initial dosage of ACCUPRIL is well tolerated or after effective management of symptomatic hypotension following initiation of therapy, the dose should then be increased gradually to 10 mg once daily, then 20 mg once daily, and to 40 mg per day given in 2 equally divided doses, depending on the patient's response. The maximum daily dose is 40 mg.

The dose titration may be done at weekly intervals, as indicated by the presence of residual signs or symptoms of heart failure.

Renal Impairment or Hyponatremia: Kinetic data indicate that ACCUPRIL elimination is dependent on the level of renal function. The recommended initial dose of ACCUPRIL is 5 mg in patients with a creatinine clearance of 30- 60 mL/min and 2.5 mg in patients with a creatinine clearance of 10-30 mL/min. There is insufficient data for dosage recommendation in patients with a creatinine clearance <10 mL/min. If the initial dose is well tolerated, ACCUPRIL may be administered the following day as a 2x daily regimen. In the absence of excessive hypotension or significant deterioration of renal function, the dose may be increased at weekly intervals based on clinical and hemodynamic response (See WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS).

On ne dispose pas de données en ce qui concerne le surdosage d'ACCUPRIL. Les manifestations cliniques les plus probables consisteraient en des symptômes imputables à l'hypotension artérielle grave, qu'on doit normalement traiter par expansion volumique à l'aide d'une solution de chlorure de sodium à 0,9 % administrée par voie intraveineuse. L'hémodialyse et la dialyse péritonéale ont peu d'effet sur l'élimination du quinapril et du quinaprilate.

Mechanism of Action

ACCUPRIL (quinapril hydrochloride) is a nonpeptide, nonsulphydryl inhibitor of angiotensin converting enzyme (ACE), which is used in the treatment of hypertension.

ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor angiotensin II. After absorption, quinapril is rapidly de-esterified to quinaprilat (quinapril diacid), its principal active metabolite. Its primary mode of action is to inhibit circulating and tissue ACE, thereby decreasing vasopressor activity and aldosterone secretion. Although the decrease in aldosterone is small, it results in a small increase in serum K+ (see WARNINGS AND PRECAUTIONS). Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity. Although ACCUPRIL had antihypertensive activity in all races studied, black hypertensive patients (usually a low-renin hypertensive population) had a smaller average response to ACE inhibitor monotherapy than non-black patients.

ACE is identical to kininase II. Thus, quinapril may interfere with the degradation of bradykinin, a potent peptide vasodilator. However, it is not known whether this system contributes to the therapeutic effects of ACCUPRIL.

In animal studies, the antihypertensive effect of quinapril outlasts its inhibitory effect on circulating ACE. Tissue ACE inhibition more closely correlates with the duration of antihypertensive effects and this may be related to enzyme binding characteristics.

Pharmacodynamics

Hypertension

Administration of 10-40 mg of ACCUPRIL to patients with essential hypertension results in a reduction of both sitting and standing BP with minimal effect on heart rate. Antihypertensive activity commences within 1 hour with peak effects usually achieved by 2-4 hours after dosing. Achievement of maximum BP lowering effects may require 2 weeks of therapy in some patients. At the recommended doses, antihypertensive effects are maintained throughout the 24-hour dosing interval in most patients. While the dose response relationship is relatively flat, a dose of 40 mg was somewhat more effective at trough than 10-20 mg, and 2x daily dosing tended to give a somewhat lower BP than 1x daily dosing with the same total daily dose. The antihypertensive effect of ACCUPRIL was maintained during long-term therapy with no evidence of loss of effectiveness.

Hemodynamic assessments in patients with essential hypertension indicate that BP reduction produced by quinapril is accompanied by a reduction in total peripheral resistance and renal vascular resistance with little or no change in heart rate and cardiac index. There was an increase in renal blood flow which was not significant. Little or no change in glomerular filtration rate (GFR) or filtration fraction was observed. Quinapril has been shown to reduce microalbuminuria in patients with essential hypertension independently of changes in systemic BP.

When ACCUPRIL is given together with thiazide-type diuretics, the antihypertensive effects are approximately additive.

Congestive heart failure

Administration of ACCUPRIL to patients with congestive heart failure (CHF) reduces peripheral vascular resistance, systolic and diastolic BP, pulmonary capillary wedge pressure, and increases cardiac output. The onset of effects was observed within 1 hour and maximal effects occurred at 1.25- 4 hours after administration of ACCUPRIL. Peak hemodynamic effects correlated well with peak plasma levels of quinaprilat (1- 4 hours after administration).

Exercise tolerance was improved with ACCUPRIL therapy.

The effect of ACCUPRIL on survival in patients with heart failure has not been evaluated.

Pharmacokinetics

Following oral administration of ACCUPRIL, peak plasma concentrations of quinapril occur within 1 hour. Based on the recovery of quinapril and its metabolites in urine, the extent of absorption is ≥60%. Following absorption, quinapril is de-esterified to its major active metabolite, quinaprilat (quinapril diacid) a potent ACE inhibitor, and to minor inactive metabolites. Quinapril has an apparent half-life in plasma of approximately 1 hour. Peak plasma quinaprilat concentrations occur approximately 2 hours after an oral dose of ACCUPRIL. Quinaprilat is eliminated primarily by renal excretion and has an effective accumulation half-life of approximately 3 hours. Quinaprilat has an elimination half-life in plasma of approximately 2 hours with a prolonged terminal phase of 25 hours. Approximately 97% of either quinapril or quinaprilat circulating in plasma is bound to proteins.

Pharmacokinetic studies in patients with end-stage renal disease on chronic hemodialysis or continuous ambulatory peritoneal dialysis indicate that dialysis has little effect on the elimination of quinapril and quinaprilat.

The disposition of quinapril and quinaprilat in patients with renal insufficiency is similar to that in patients with normal renal function until creatinine clearance is ≤60 mL/min. With creatinine clearance <60 mL/min, peak and trough quinaprilat concentrations increase, apparent half-life increases, and time to steady state may be delayed. The elimination of quinaprilat may be reduced in elderly patients (>65 years) and in those with heart failure; this reduction is attributable to decrease in renal function (see DOSAGE and ADMINISTRATION). Quinaprilat concentrations are reduced in patients with alcoholic cirrhosis due to impaired de-esterification of quinapril.

The rate and extent of quinapril absorption are diminished moderately (approximately 25-30%) when ACCUPRIL tablets are administered during a high-fat meal. However, no effect on quinapril absorption occurs when taken during a regular meal.

Studies in rats indicate that quinapril and its metabolites do not cross the blood-brain barrier.

Special Populations and Conditions

Geriatrics:

Therapeutic effects appear to be the same for elderly (>65 years of age) and younger adult patients given the same daily dosages, with no increase in AEs in elderly patients.

Race:

The antihypertensive effect of ACE inhibitors is generally lower in black than in non-black patients.

Store at controlled room temperature, 15-30^oC. Protect from moisture. Dispense in well-closed containers.

Les comprimés d'ACCUPRIL (chlorhydrate de quinapril) se présentent comme suit :

ACCUPRIL à 5 mg : Dosés à 5 mg de quinapril. Comprimés bruns, pelliculés, de forme elliptique, marqués en creux de l'inscription « PD 527 » sur une face et sur l'autre, du chiffre « 5 ». Flacons de 90 comprimés.

ACCUPRIL à 10 mg : Dosés à 10 mg de quinapril. Comprimés bruns, pelliculés, de forme triangulaire, marqués en creux de l'inscription « PD 530 » sur une face et sur l'autre, du chiffre « 10 ». Flacons de 90 comprimés.

ACCUPRIL à 20 mg : Dosés à 20 mg de quinapril. Comprimés bruns, pelliculés, de forme ronde, marqués en creux de l'inscription « PD 532 » sur une face et sur l'autre, du chiffre « 20 ». Flacons de 90 comprimés.

ACCUPRIL à 40 mg : Dosés à 40 mg de quinapril. Comprimés bruns, pelliculés, de forme elliptique, marqués en creux de l'inscription « PD 535 » sur une face et sur l'autre, du chiffre « 40 ». Flacons de 90 comprimés.

Composition

Les comprimés d'ACCUPRIL sont dosés à 5 mg, 10 mg, 20 mg ou 40 mg de quinapril (sous forme de chlorhydrate). Chaque comprimé contient aussi les substances suivantes : cire de candelilla, crospovidone, gélatine, hydroxypropylcellulose, hydroxypropylméthylcellulose, lactose, carbonate de magnésium, stéarate de magnésium, polyéthylèneglycol, oxyde de fer rouge synthétique et dioxyde de titane.

ACCUPRIL is contraindicated in:

• Patients who are hypersensitive to the drug or to any ingredient in the formulation. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph.
• Patients with a history of angioedema related to previous treatment with an angiotensin converting enzyme (ACE) inhibitor (see WARNINGS AND PRECAUTIONS, General, Head and Neck Angioedema).
• Women who are pregnant, intend to become pregnant, or of childbearing potential who are not using adequate contraception (see WARNINGS AND PRECAUTIONS, Special Populations, Pregnant Women and ADVERSE REACTIONS).
• Nursing women (see WARNINGS AND PRECAUTIONS, Special Populations, Nursing Women).
• Combination with aliskiren-containing medicines in patients with:
  • diabetes mellitus (type 1 or type 2),
  • moderate to severe kidney insufficiency (GFR < 60 mL/min/1.73 m²),
  • hyperkalemia (> 5mMol/L) or
  • congestive heart failure who are hypotensive (see WARNINGS AND PRECAUTIONS, Dual blockade of the Renin-Angiotensin System (RAS) and Renal Impairment, and DRUG INTERACTIONS, Aliskiren-containing medicines and Angiotensin receptor blockers (ARBs) or other ACE inhibitors).

• Combination with angiotensin receptor blockers (ARBs) or other ACE inhibitors in patients with:
  • diabetes with end organ damage,
  • moderate to severe kidney insufficiency (GFR < 60 mL/min/1.73m²),
  • hyperkalemia (> 5mMol/L) or
  • congestive heart failure who are hypotensive (see DRUG INTERACTIONS, Angiotensin receptor blockers (ARBs) or other ACE inhibitors).
• Patients with hereditary problems of galactose intolerance, glucose-galactose malabsorption or the Lapp lactase deficiency as ACCUPRIL contains lactose (see WARNINGS AND PRECAUTIONS, Sensitivity/Resistance).

Mode d’action

ACCUPRIL (chlorhydrate de quinapril) est un inhibiteur non peptidique et non sulfhydrylique de l'enzyme de conversion de l'angiotensine (ECA), utilisé dans le traitement de l'hypertension artérielle.

L'ECA est une dipeptidase peptidylique qui catalyse la transformation de l'angiotensine I en angiotensine II, substance vasoconstrictrice. Après son absorption, le quinapril est rapidement désestérifié en quinaprilate (diacide de quinapril), son principal métabolite actif. Il agit surtout par inhibition de l'ECA circulante et tissulaire, et diminue l'activité vasopressive et la sécrétion d'aldostérone. Bien que la diminution de sécrétion d'aldostérone soit faible, elle se traduit entre autres par une petite élévation du taux plasmatique de K+ (voir MISES EN GARDE ET PRÉCAUTIONS). La levée du rétrocontrôle négatif de l'angiotensine II sur la sécrétion de rénine entraîne une augmentation de l'activité rénine plasmatique. Bien qu'ACCUPRIL ait fait la preuve de son action antihypertensive dans toutes les races étudiées, la proportion moyenne des sujets hypertendus ayant répondu favorablement à la monothérapie par inhibiteur de l'ECA est plus petite pour la race noire (qui a généralement un faible taux de rénine plasmatique) que pour les autres races. L'ECA est identique à la kininase II. Il se peut, par conséquent, que le quinapril entrave la dégradation de la bradykinine, vasodilatateur peptidique puissant. On ne sait toutefois pas si ce mécanisme concourt aux effets thérapeutiques d'ACCUPRIL.

Selon les études faites sur l'animal, l'effet antihypertensif du quinapril dure plus longtemps que son effet inhibiteur sur l'ECA circulante. L'inhibition de l'ECA tissulaire est davantage en corrélation avec la durée des effets antihypertensifs, ce qui peut s'expliquer par les caractéristiques de liaison à l'enzyme

Pharmacodynamie

Hypertension

L'administration d'ACCUPRIL à des doses de 10 à 40 mg à des patients souffrant d'hypertension artérielle essentielle se traduit par une baisse de la tension artérielle aussi bien en position assise que debout, avec très peu d'effet sur la fréquence cardiaque. L'action antihypertensive commence en l'espace d'une heure et atteint habituellement son maximum de 2 à 4 heures après la prise du médicament. Il faut parfois jusqu'à deux semaines de traitement pour atteindre la baisse tensionnelle maximale chez certains patients. Aux doses recommandées, les effets antihypertensifs se maintiennent, dans la plupart des cas, pendant tout l'intervalle posologique de 24 heures. Quoique la courbe dose-réponse soit plutôt aplatie, une dose de 40 mg s'est révélée un peu plus efficace au moment du creux que des doses de 10 à 20 mg. Deux prises par jour ont aussi eu tendance à abaisser un peu plus la pression artérielle qu'une seule prise par jour, avec la même dose totale quotidienne. Pendant le traitement de longue durée, l'effet antihypertensif d'ACCUPRIL s'est maintenu, sans signe de perte d'efficacité.

Les explorations hémodynamiques chez des patients souffrant d'hypertension artérielle essentielle indiquent que la diminution de la pression artérielle due au quinapril s'accompagne d'une baisse de la résistance vasculaire périphérique et de la résistance vasculaire rénale, en modifiant peu ou sans modifier du tout la fréquence et l'index cardiaques. On a constaté une augmentation de la circulation rénale, jugée non significative, ainsi que des changements minimes, voire nuls, dans la filtration glomérulaire (FG) ou la fraction de filtration.

Il a été démontré que le quinapril diminue la microalbuminurie chez les patients souffrant d’hypertension essentielle, et ce, indépendamment des variations de la tension artérielle systémique.

Quand ACCUPRIL est administré en association avec des diurétiques thiazidiques, les effets antihypertensifs sont à peu près additifs.

Insuffisance cardiaque congestive

ACCUPRIL, administré à des patients souffrant d'insuffisance cardiaque congestive (ICC), abaisse la résistance vasculaire périphérique, les pressions artérielles systolique et diastolique ainsi que la pression capillaire pulmonaire, et augmente le débit cardiaque. On a observé que ces effets commençaient en l'espace d'une heure et atteignaient leur maximum de 1,25 à 4 heures après l'administration d'ACCUPRIL. Il existe une bonne corrélation entre les effets hémodynamiques maximaux et le pic plasmatique du quinaprilate (de 1 à 4 heures après l'administration).

Le traitement par ACCUPRIL a amélioré l'endurance à l'effort.

L'effet d'ACCUPRIL sur la survie des patients souffrant d'insuffisance cardiaque n'a pas été évalué.

Pharmacocinétique

Après l'administration d'ACCUPRIL par voie orale, le pic plasmatique du quinapril est atteint en une heure. D'après la quantité de quinapril et de ses métabolites retrouvée dans l'urine, on sait qu'au moins 60 % du quinapril est absorbé. Après son absorption, le quinapril est désestérifié en son principal métabolite actif, le quinaprilate (diacide de quinapril), inhibiteur puissant de l'ECA, et en d'autres métabolites inactifs mineurs. La demi-vie apparente du quinapril dans le plasma est d'environ une heure. Le pic plasmatique du quinaprilate est atteint environ 2 heures après la prise d'ACCUPRIL par voie orale. Le quinaprilate est éliminé principalement par voie rénale, avec une demi-vie d'accumulation réelle d'environ 3 heures. La demi-vie d'élimination plasmatique du quinaprilate est d'environ 2 heures, avec une phase finale prolongée de 25 heures. Le quinapril et le quinaprilate circulants se fixent sur les protéines plasmatiques dans une proportion d'environ 97 %.

Les études de pharmacocinétique chez des sujets en phase terminale de maladie rénale, soumis à une hémodialyse chronique ou à une dialyse péritonéale ambulatoire continue, indiquent que la dialyse a peu d'effet sur l'élimination du quinapril et du quinaprilate.

L'élimination du quinapril et du quinaprilate chez les personnes souffrant d'insuffisance rénale est semblable à celle observée lorsque la fonction rénale est normale, jusqu'à ce que la clairance de créatinine baisse à 60 mL/min ou moins. Lorsque la clairance de créatinine est inférieure à 60 mL/min, le pic et le creux sériques du quinaprilate augmentent, de même que sa demi-vie apparente, et le délai nécessaire pour atteindre l'état d'équilibre peut être plus long. L'élimination du quinaprilate peut être moindre chez les sujets âgés (> 65 ans) et chez ceux souffrant d'insuffisance cardiaque; cette diminution est imputable à une insuffisance rénale (voir POSOLOGIE ET MODE D’ADMINISTRATION). La concentration plasmatique du quinaprilate diminue en présence de cirrhose alcoolique, par manque de désestérification du quinapril.

Le taux et le degré d'absorption du quinapril diminuent modérément (d'environ 25 à 30 %) quand les comprimés d'ACCUPRIL sont pris pendant un repas riche en matières grasses. Il n'y a cependant pas d'effet sur l'absorption du quinapril quand il est pris avec un repas ordinaire.

Selon les études chez le rat, le quinapril et ses métabolites ne franchissent pas la barrière hématoencéphalique.

Populations particulières et états pathologiques

Personnes âgées :

Les effets thérapeutiques semblent être les mêmes chez les sujets âgés (> 65 ans) que chez les adultes plus jeunes prenant la même dose par jour, sans augmentation des effets indésirables chez les personnes âgées.

Race :

L'effet antihypertensif des inhibiteurs de l'enzyme de conversion de l'angiotensine est généralement inférieur chez les sujets de race noire que chez ceux des autres races.

Interactions médicament-médicament

Légende : E = Étude de cas; ECR = Étude de cohorte rétrospective; EC = Essai clinique; T = Théorique

Interactions médicament-aliment

Le taux et le degré d'absorption du quinapril diminuent modérément (d'environ 25 à 30 %) quand les comprimés d'ACCUPRIL sont pris pendant un repas riche en matières grasses. Il n'y a cependant pas d'effet sur l'absorption du quinapril quand il est pris avec un repas ordinaire.

Interactions médicament-herbe médicinale

Aucune interaction n’a été établie avec des produits à base d’herbes médicinales.

Effets du médicament sur les résultats des épreuves de laboratoire

Aucun effet du quinapril sur les épreuves de laboratoire n’a été démontré.

Effet du médicament sur le style de vie

Aucun effet de cette nature n'a été relevé.

ACCUPRIL est contre-indiqué :

• chez les patients hypersensibles à ce médicament ou à l'un des ingrédients de la préparation (voir PRÉSENTATION, COMPOSITION ET CONDITIONNEMENT pour connaître la liste complète des ingrédients);
• chez les patients ayant déjà eu un œdème angioneurotique lors d'un traitement antérieur par un inhibiteur de l'enzyme de conversion de l’angiotensine (ECA) (voir MISES EN GARDE ET PRÉCAUTIONS, Généralités, Œdème angioneurotique de la tête et du cou);
• chez les femmes enceintes ou qui prévoient le devenir, de même que chez les femmes aptes à procréer qui n’utilisent pas de méthode contraceptive efficace (voir MISES EN GARDE ET PRÉCAUTIONS, Populations particulières, Femmes enceintes et EFFETS INDÉSIRABLES);
• chez les femmes qui allaitent (voir MISES EN GARDE ET PRÉCAUTIONS, Populations particulières, Femmes qui allaitent);
• en concomitance avec des médicaments qui contiennent de l’aliskirène chez les patients atteints :
  • de diabète (type 1 ou 2),
  • d’insuffisance rénale modérée ou grave (filtration glomérulaire < 60 mL/min/1,73 m²),
  • d’hyperkaliémie (> 5 mmol/L),
  • d’insuffisance cardiaque qui sont aussi hypotendus (voir MISES EN GARDE ET PRÉCAUTIONS, Double inhibition du système rénine-angiotensine et Insuffisance rénale, et INTERACTIONS MÉDICAMENTEUSES, Médicaments contenant de l’aliskirène et Antagonistes des récepteurs de l’angiotensine ou autres inhibiteurs de l’ECA);
• en concomitance avec des antagonistes des récepteurs de l’angiotensine ou d’autres inhibiteurs de l’ECA chez des patients atteints :
  • de diabète et présentant des lésions des organes cibles,
  • d’insuffisance rénale modérée ou grave (filtration glomérulaire < 60 mL/min/1,73 m²),
  • d’hyperkaliémie (> 5 mmol/L),
  • d’insuffisance cardiaque qui sont aussi hypotendus (voir INTERACTIONS MÉDICAMENTEUSES, Antagonistes des récepteurs de l’angiotensine ou autres inhibiteurs de l’ECA);
• chez les patients atteints d’une maladie héréditaire comme une intolérance au galactose, un syndrome de malabsorption du glucose-galactose ou un déficit en lactase de Lapp, étant donné qu’ACCUPRIL contient du lactose (voir MISES EN GARDE ET PRÉCAUTIONS, Sensibilité et résistance)

Conserver à une température ambiante contrôlée de 15 à 30 °C. Craint l'humidité. À remettre dans des récipients bien fermés.

La posologie d'ACCUPRIL (chlorhydrate de quinapril) doit être adaptée à chaque cas.

Hypertension artérielle

Au moment de la mise en route du traitement, il faut tenir compte du traitement antihypertensif récent, du degré d'hypertension artérielle et de la restriction de sel. Les autres antihypertenseurs employés avec ACCUPRIL peuvent aussi nécessiter une adaptation posologique.

Monothérapie
La dose initiale d'ACCUPRIL recommandée chez les patients ne prenant pas de diurétique est de 10 mg une fois par jour. On peut envisager le recours à une dose initiale de 20 mg une fois par jour chez les patients qui ne sont ni âgés, ne présentant aucune atteinte rénale ni insuffisance cardiaque concomitante, et qui ne présentent pas de déplétion du volume des liquides (voir MISES EN GARDE ET PRÉCAUTIONS, Système cardiovasculaire, Hypotension). La posologie doit ensuite être adaptée selon l'effet du traitement sur la pression artérielle, généralement à intervalles de deux à quatre semaines. Il ne faut pas dépasser 40 mg par jour.

Chez certains patients traités une fois par jour, l'effet antihypertensif peut diminuer vers la fin de l'intervalle posologique. On peut en juger en mesurant la tension artérielle tout de suite avant la prise du médicament, ce qui permet de déterminer si la stabilisation de la pression artérielle est bien maintenue pendant 24 heures. Dans la négative, on doit envisager soit deux prises par jour pour une même dose totale par 24 heures, soit une augmentation de la dose. Lorsqu'on n'obtient pas une maîtrise suffisante de la pression artérielle à l'aide d'ACCUPRIL seul, on peut y ajouter un diurétique. Après l'adjonction du diurétique, il est parfois possible de diminuer la dose d'ACCUPRIL.

Traitement diurétique concomitant : Une hypotension symptomatique peut parfois survenir après la dose initiale d'ACCUPRIL. Elle est plus susceptible d'être présente chez les patients prenant déjà un diurétique. Il est conseillé d'interrompre, si c'est possible, l'administration du diurétique pendant deux ou trois jours avant de commencer le traitement par ACCUPRIL, en vue de diminuer le risque de réaction hypotensive (voir MISES EN GARDE ET PRÉCAUTIONS, Système cardiovasculaire, Hypotension). Si une telle interruption du diurétique est impossible, on doit administrer une dose initiale de 5 mg d'ACCUPRIL avec étroite surveillance médicale pendant quelques heures ou jusqu'à la stabilisation de la pression artérielle. On adaptera ensuite graduellement la posologie d'ACCUPRIL (comme il est expliqué ci-dessus) jusqu'à l'obtention d'un effet optimal.

Adaptation posologique chez les personnes souffrant d'insuffisance rénale : Consulter MISES EN GARDE ET PRÉCAUTIONS, Réactions anaphylactoïdes au cours de la dialyse pour l'utilisation chez les patients en hémodialyse. Le quinapril doit être administré les jours où le patient ne subit pas de dialyse.

On augmentera ensuite graduellement la posologie (comme il est expliqué ci-dessus) jusqu'à l'obtention d'un effet optimal.

Posologie pour les personnes âgées (> 65 ans) : La dose initiale d'ACCUPRIL recommandée chez les personnes âgées est de 10 mg une fois par jour (en fonction de l'état de la fonction rénale); on doit ensuite augmenter graduellement la dose (comme il est expliqué ci-dessus) jusqu'à l'obtention d'un effet optimal.

Insuffisance cardiaque congestive

ACCUPRIL est indiqué comme traitement adjuvant aux diurétiques et/ou aux glucosides cardiaques. La mise en route du traitement doit se faire avec étroite surveillance médicale. Il faut surveiller la pression artérielle et la fonction rénale avant et pendant le traitement par ACCUPRIL, car il y a eu des cas d'hypotension grave et, plus rarement, d'insuffisance rénale consécutive (voir MISES EN GARDE ET PRÉCAUTIONS, Système cardiovasculaire, Hypotension).

Lors de la mise en route du traitement, il faut tenir compte d'un traitement diurétique récent et de la possibilité d'une déplétion hydrosodée grave. Pour réduire le risque de réaction hypotensive, il est conseillé de diminuer, si c'est possible, la dose de diurétique avant de commencer le traitement par ACCUPRIL. La kaliémie est aussi à surveiller (voir MISES EN GARDE ET PRÉCAUTIONS, INTERACTIONS MÉDICAMENTEUSES).

La dose initiale recommandée est de 5 mg une fois par jour, à administrer avec étroite surveillance médicale pour déterminer l'effet initial sur la pression artérielle. Après cette dose initiale, il faut garder le patient en observation pendant au moins deux heures ou jusqu'à ce que sa pression artérielle ait été stabilisée pendant au moins une heure supplémentaire (voir MISES EN GARDE ET PRÉCAUTIONS, Système cardiovasculaire, Hypotension). Cette dose peut améliorer les symptômes d'insuffisance cardiaque, mais il faut généralement de plus fortes doses pour augmenter la durée d'endurance à l'effort. Par conséquent, lorsque la dose initiale d'ACCUPRIL est bien tolérée ou que l'hypotension symptomatique est bien maîtrisée après le début du traitement, on doit augmenter la posologie graduellement à 10 mg une fois par jour. On peut ensuite augmenter la posologie à 20 mg une fois par jour, puis à 40 mg divisés en deux prises égales, en fonction du résultat thérapeutique. La dose quotidienne maximale est de 40 mg.

L'adaptation posologique peut se faire à intervalles hebdomadaires, selon les besoins indiqués par la persistance de signes ou de symptômes d'insuffisance cardiaque.

Insuffisance rénale ou hyponatrémie : Selon les données pharmacocinétiques, l'élimination d'ACCUPRIL dépend de la fonction rénale. La dose initiale d'ACCUPRIL recommandée est de 5 mg chez les patients dont la clairance de créatinine se situe entre 30 et 60 mL/min et de 2,5 mg chez ceux dont la clairance de créatinine est entre 10 et 30 mL/min. Les données sont insuffisantes pour recommander une dose d'ACCUPRIL chez les patients dont la clairance de créatinine est < 10 mL/min. Lorsque le patient tolère bien la première dose, on peut administrer ACCUPRIL deux fois par jour à partir du jour suivant. En l'absence d'hypotension excessive ou d'une détérioration importante de la fonction rénale, on peut ensuite augmenter la dose à intervalles hebdomadaires, selon la réponse clinique et hémodynamique du patient (voir MISES EN GARDE ET PRÉCAUTIONS et EFFETS INDÉSIRABLES).

General

Angioedema

Angioedema has been reported in patients treated with ACE inhibitors, including quinapril. Angioedema associated with laryngeal involvement may be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, treatment with ACCURETIC (quinapril hydrochloride and hydrochlorothiazide) should be discontinued immediately, the patient treated appropriately in accordance with accepted medical care, and carefully observed until the swelling disappears. In instances where swelling is confined to the face and lips, the condition generally resolves without treatment, although antihistamines may be useful in relieving symptoms. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy (including but not limited to 0.3 to 0.5 mL of subcutaneous epinephrine solution 1:1000) should be administered promptly (see ADVERSE REACTIONS).

The incidence of angioedema during ACE inhibitor therapy has been reported to be higher in black than in non-black patients.

Patients taking concomitant mTOR inhibitor (e.g. temsirolimus) or concomitant DPP-IV inhibitor (e.g. sitagliptin) therapy may be at increased risk for angioedema. Caution should be used when either initiating ACE inhibitor therapy in patients already taking mTOR or DPP-IV inhibitor or vice versa (see DRUG INTERACTIONS).

Patients with a history of angioedema related or unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see CONTRAINDICATIONS).

Cardiovascular

Dual blockade of the Renin-Angiotensin System (RAS)

Dual blockade of the Renin-Angiotensin System (RAS): There is evidence that co-administration of angiotensin converting enzyme (ACE) inhibitors, such as ACCURETIC, or of angiotensin receptor antagonists (ARBs) with aliskiren increases the risk of hypotension, syncope, stroke, hyperkalemia and deterioration of renal function, including acute renal failure, in patients with diabetes mellitus (type 1 or type 2) and/or moderate to severe kidney insufficiency (GFR < 60 mL/min/1.73 m²). Therefore, the use of ACCURETIC in combination with aliskiren-containing drugs is contraindicated in these patients (see CONTRAINDICATIONS).
Further, co-administration of ACE inhibitors, including ACCURETIC, with other agents blocking the RAS, such as ARBs or aliskiren-containing drugs, is generally not recommended in other patients, since such treatment has been associated with an increased incidence of severe hypotension, acute renal failure, and hyperkalemia. Administration should be limited to individually defined cases with close monitoring of renal function and blood potassium levels (see CONTRAINDICATIONS).

Hypotension

Symptomatic hypotension has occurred after administration of quinapril, usually after the first or second dose or when the dose was increased. It is more likely to occur in patients who are volume depleted by diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. In patients with ischemic heart or cerebrovascular disease, an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident (See ADVERSE REACTIONS). Because of the potential fall in blood pressure in these patients, therapy with ACCURETIC should be started under close medical supervision. Such patients should be followed closely for the first weeks of treatment and whenever the dose of ACCURETIC is increased. In patients with severe congestive heart failure, with or without associated renal insufficiency, excessive hypotension has been observed and may be associated with oliguria and/or progressive azotemia, and rarely with acute renal failure and/or death.

If hypotension occurs, the patient should be placed in supine position and, if necessary, receive an intravenous infusion of 0.9% sodium chloride. A transient hypotensive response is not a contraindication to further doses which usually can be given without difficulty once the blood pressure has increased after volume expansion. If symptoms persist, the dosage should be reduced or the drug discontinued.

Valvular Stenosis

There is concern on theoretical grounds that patients with aortic stenosis might be at particular risk of decreased coronary perfusion when treated with vasodilators because they do not develop as much afterload reduction.

Endocrine and Metabolism

Initial and periodic determination of serum electrolytes should be performed at appropriate intervals to detect possible electrolyte imbalance.

Hyperkalemia/Hypokalemia

Quinapril: Elevated serum potassium (>5.7 mMol/L) was observed in approximately 2% of patients receiving quinapril. In most cases these were isolated values which resolved despite continued therapy. Hyperkalemia was a cause of discontinuation of therapy in <0.1% of hypertensive patients. Risk factors for the development of hyperkalemia may include renal insufficiency, diabetes mellitus, and the concomitant use of agents to treat hypokalemia (see WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests, Serum Electrolytes, ADVERSE REACTIONS and DRUG INTERACTIONS, Agents Increasing Serum Potassium). The addition of a potassium-sparing diuretic to ACCURETIC, which contains a diuretic, is not recommended.

Hydrochlorothiazide: Treatment with thiazide diuretics has been associated with hypokalemia. Hypokalemia can also sensitize or exaggerate the response of the heart to the toxic effects of digitalis. The risk of hypokalemia is greatest in patients with cirrhosis of the liver, in patients experiencing a brisk diuresis, in patients who are receiving inadequate oral intake of electrolytes, and in patients receiving concomitant therapy with corticosteroids or ACTH or with other drugs known to increase the risk of hypokalemia induced by thiazide diuretics (e.g. aminoglycoside antibiotics, cisplatin, foscarnet, amphotericin B and loop diuritics (furosemide)).

Quinapril/Hydrochlorothiazide: The opposite effects of hydrochlorothiazide and quinapril on serum potassium may approximately balance each other in many patients so that no net effect will be seen. In other patients, one or the other effect may be dominant.

Other electrolytes imbalances

Hydrochlorothiazide: In addition to hypokalemia, treatment with thiazide diuretics has also been associated with hyponatremia and hypochloremic alkalosis. These disturbances have sometimes been manifest as one or more of the following: dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, muscular fatigue, hypotension, oliguria, tachycardia, nausea, confusion, seizures and vomiting.
Chloride deficits secondary to thiazide therapy are generally mild and require specific treatment only under extraordinary circumstances (e.g. in liver disease or renal disease). Dilutional hyponatremia may occur in edematous patients, especially in hot weather; appropriate therapy is water restriction rather than administration of salt, except when the hyponatremia is life threatening. In actual salt depletion, replacement of salt is the therapy of choice.
Thiazides may decrease calcium excretion. Thiazides may cause intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcemia may be evidence of hidden hypoparathyroidism. In a few patients on prolonged thiazide therapy, pathological changes in the parathyroid gland have been observed, with hypercalcemia and hypophosphatemia. More serious complications of hyperparathyroidism (renal lithiasis, bone resorption, and peptic ulceration) have not been seen. Thiazides should be discontinued before performing tests for parathyroid function.

Thiazides increase the urinary excretion of magnesium, and hypomagnesaemia may result.

Hypoglycemia/Hyperglycemia and Diabetes

Quinapril: ACE inhibitors may reduce insulin resistance and may lead to hypoglycemia in diabetic patients on insulin or oral hypoglycemic agents; closer monitoring of diabetic patients may be required.

Hydrochlorothiazide: Thiazide-induced hyperglycemia may compromise blood sugar control. Depletion of serum potassium augments glucose intolerance. Monitor glycemic control, supplement potassium, if necessary, to maintain appropriate serum potassium levels, and adjust diabetes medications as required (see DRUG INTERACTIONS, Antidiabetic agents (e.g. insulin, oral hypoglycemic agents, sitagliptin).
Overt diabetes may be precipitated in susceptible individuals.

Other metabolic parameters

Hyperuricemia may occur, or acute hyperuricemia may be precipitated, in certain patients receiving thiazide therapy.

Increase in cholesterol, triglyceride and glucose levels may be associated with thiazide diuretic therapy.

Thiazides may decrease serum PBI levels without signs of thyroid disturbance.

Hematologic

Neutropenia/Agranulocytosis

Agranulocytosis and bone marrow depression have been caused by ACE inhibitors. Agranulocytosis did occur during quinapril treatment in one patient with a history of neutropenia during previous captopril therapy. Periodic monitoring of white blood cell counts should be considered, especially in patients with collagen vascular disease and/or renal disease.

Hepatic

Impairment of Liver Function

Hepatitis (hepatocellular and/or cholestatic), elevations of liver enzymes and/or serum bilirubin have occurred during therapy with other ACE inhibitors in patients with or without pre-existing liver abnormalities. In most cases the changes were reversed on discontinuation of the drug.

Elevations of liver enzymes and/or serum bilirubin have been reported for ACCURETIC (see ADVERSE REACTIONS). Should the patient receiving ACCURETIC experience any unexplained symptoms particularly during the first weeks or months of treatment, it is recommended that a full set of liver function tests and any other necessary investigation be carried out. Discontinuation of ACCURETIC should be considered when appropriate.

There are no adequate studies in patients with cirrhosis and/or liver dysfunction. ACCURETIC should be used with particular caution in patients with pre-existing liver abnormalities. In such patients baseline liver function tests should be obtained before administration of the drug and close monitoring of response and metabolic effects should apply.

Patients with Impaired Liver Function

ACCURETIC should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma. Also, since the metabolism of quinapril to quinaprilat is normally dependent upon hepatic esterase, patients with impaired liver function could develop markedly elevated plasma levels of quinapril.

Immune

Anaphylactoid Reactions during Membrane Exposure

Anaphylactoid reactions have been reported in patients dialysed with high-flux membranes (e.g.: polyacrylonitrile [PAN]) and treated concomitantly with an ACE inhibitor. Dialysis should be stopped immediately if symptoms such as nausea, abdominal cramps, burning, angioedema, shortness of breath and severe hypotension occur. Symptoms are not relieved by antihistamines. In these patients consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.

Anaphylactoid Reactions during LDL Apheresis

Rarely, patients receiving ACE inhibitors during low density lipoprotein apheresis with dextran sulfate have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding the ACE inhibitor therapy prior to each apheresis.

Anaphylactoid Reactions during Desensitization

There have been isolated reports of patients experiencing sustained life threatening anaphylactoid reactions while receiving ACE inhibitors during desensitizing treatment with hymenoptera (bees, wasps) venom. In the same patients, these reactions have been avoided when ACE inhibitors were temporarily withheld for at least 24 hours, but they have reappeared upon inadvertent rechallenge to an ACE inhibitor.

Hypersensitivity to Hydrochlorothiazide

Sensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma.

Nitritoid Reactions-Gold

Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and symptomatic hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including ACCURETIC (see DRUG INTERACTIONS).

Systemic Lupus Erythematosus

Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus.

Ophthalmologic

Acute Myopia and Secondary Angle-Closure Glaucoma related to Hydrochlorothiazide

Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss.
The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

Peri-Operative Considerations

Surgery/Anaesthesia

In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, ACE inhibitors will block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.

Renal

Azotemia

Azotemia may be precipitated or increased by hydrochlorothiazide. Cumulative effects of the drug may develop in patients with impaired renal function. If increasing azotemia and oliguria occur, ACCURETIC should be discontinued.

Renal Impairment

The use of ACE inhibitors, including ACCURETIC, with ARBs or aliskiren-containing drugs is contraindicated in patients with moderate to severe kidney insufficiency (GFR < 60 mL/min/1.73m²) (see CONTRAINDICATIONS and DRUG INTERACTIONS, Aliskiren- containing medicines and Angiotensin receptor blockers (ARBs) or other ACE inhibitors).

As a consequence of inhibiting the renin-angiotensin-aldosterone system (RAAS), changes in renal function have been seen in susceptible individuals. In patients whose renal function may depend on the activity of the RAAS, such as patients with bilateral renal artery stenosis, unilateral renal artery stenosis to a solitary kidney, or severe congestive heart failure, treatment with agents that inhibit this system has been associated with oliguria, progressive azotemia, and rarely, acute renal failure and/or death. In susceptible patients, concomitant diuretic use may further increase risk (see ADVERSE REACTIONS and DOSAGE ADMINISTRATION).

Use of ACCURETIC should be followed by the appropriate assessment of renal function (see ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION).

Thiazides may not be appropriate diuretics for use in patients with renal impairment and are ineffective at creatinine clearance values of ≤30 mL/min (i.e. moderate or severe renal insufficiency) (see ADVERSE REACTIONS and DOSAGE ADMINISTRATION).

Respiratory

Cough

A dry, persistent cough, which usually disappears only after withdrawal or lowering of the dose of quinapril has been reported. Such possibility should be considered as part of the differential diagnosis of the cough.

Sensitivity/Resistance

Due to the presence of lactose, patients with hereditary problems of galactose intolerance, glucose-galactose malabsorption or the Lapp lactase deficiency should not take ACCURETIC (see CONTRAINDICATIONS).

Special Populations

Pregnant Women

Quinapril is contraindicated in pregnancy (see CONTRAINDICATIONS and ADVERSE REACTIONS). ACE inhibitors can cause fetal and neonatal morbidity and mortality when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, ACCURETIC should be discontinued as soon as possible.

The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development.

Prematurity, and patent ductus arteriosus and other structural cardiac malfomations, as well as neurological malformations, have also been reported following exposure in the first trimester of pregnancy.

Infants with a history of in utero exposure to ACE inhibitors should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as a means of reversing hypotension and/or substituting for impaired renal function; however, limited experience with those procedures has not been associated with significant clinical benefit.

If oligohydramnios is observed, a non-stress test (NST), and/or a biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. If concerns regarding fetal well- being still persist, a contraction stress test (CST) should be considered. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Thiazides cross the placental barrier and appear in cord blood. Although studies in humans have not been done, effects to the fetus may include fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions which have occurred in the adult.

Animal Data: No fetotoxic or teratogenic effects were observed in rats at quinapril doses as high as 300 mg/kg/day (180x maximum daily human dose), despite maternal toxicity at 150 mg/kg/day. Offspring body weights were reduced in rats treated late in gestation and during lactation with doses of ≥25 mg/kg/day. Quinapril hydrochloride was not teratogenic in rabbits; however, maternal and embryo toxicity were seen in some rabbits at doses as low as 0.5 mg/kg/day and 1 mg/kg/day, respectively.
No adverse effects on fertility or reproduction were observed in rats at quinapril dose levels ≤100 mg/kg/day (60x maximum daily human dose).

Nursing Women

The presence of concentrations of ACE inhibitor has been reported in human milk. Thiazides also appear in human milk. The use of ACCURETIC is contraindicated during breast-feeding (see CONTRAINDICATIONS).

Pediatrics (<18 years of age)

The safety and effectiveness of ACCURETIC in children have not been established, therefore use in this age group is not recommended.

Monitoring and Laboratory Tests

Serum Electrolytes: Variations of serum electrolytes levels have been observed with ACCURETIC. Initial and periodic determination of serum electrolytes should be performed at appropriate intervals to detect possible electrolyte imbalance (See CONTRAINDICATIONS and WARNINGS and PRECAUTIONS).
Creatinine and Blood Nitrogen: Increases (>1.25x ULN) in serum creatinine and blood urea nitrogen (BUN) were observed in 3% and 4% respectively, of patients treated with ACCURETIC (see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION).
Hepatic: Elevations of liver enzymes and/or serum bilirubin have occurred in patients receiving ACCURETIC. If a patient receiving ACCURETIC experience any unexplained symptoms, particularly during the first weeks or months of treatment, a full set of liver function tests and any other investigation should be carried out. Discontinuation of ACCURETIC should be considered when appropriate. In patients with pre-existing liver abnormalities, baseline liver function tests should be obtained before administration of the drug. The response and metabolic effects should be closely monitored (see WARNINGS AND PRECAUTIONS).
Glucose: Elevations in glucose values have occurred. Monitor glycemic control, supplement potassium, if necessary, to maintain appropriate serum potassium levels, and adjust diabetes medications as required (see WARNINGS AND PRECAUTIONS, Endocrine and Metabolism, Hypoglycemia/Hyperglycemia and Diabetes and DRUG INTERACTIONS, Antidiabetic agents (e.g. insulin, oral hypoglycemic agents, sitagliptin).
Triglyceride: Elevations in triglyceride values have occurred (see WARNINGS AND PRECAUTIONS, Endocrine and Metabolism, Other metabolic parameters).
Serum Uric Acid: Elevations in serum uric acid values have occurred (see WARNINGS AND PRECAUTIONS, Endocrine and Metabolism, Other metabolic parameters).
Hematology: Possibly clinically important increases and decreases in hematology parameters have occurred. Periodic monitoring of white blood cell counts should be considered, especially in patients with collagen vascular disease and/or renal disease (see WARNINGS AND PRECAUTIONS, Hematologic, Neutropenia/Agranulocytosis).
Other laboratory test values with clinically important deviations during controlled and uncontrolled trials included: Magnesium, Cholesterol, PBI, Parathyroid Function Tests and Calcium (see WARNINGS AND PRECAUTIONS, Endocrine and Metabolism, Other electrolytes imbalances and Other metabolic parameters).

ACCURETIC is contraindicated in:

• Patients who are hypersensitive to the drug or to any ingredient in the formulation. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph.
• Patients with a history of angioedema related to previous treatment with an angiotensin converting enzyme (ACE) inhibitor (see WARNINGS AND PRECAUTIONS, General, Angioedema).
• Patients hypersensitive to other sulfonamide-derived drugs because of the hydrochlorothiazide component.
• Patients with anuria.
• Women who are pregnant, intend to become pregnant, or of childbearing potential who are not using adequate contraception (see WARNINGS AND PRECAUTIONS, Special  Populations, Pregnant Women and ADVERSE REACTIONS).
• Nursing women (see WARNINGS AND PRECAUTIONS, Special Populations, Nursing Women).
• Combination with aliskiren-containing medicines in patients with
  • diabetes mellitus (type 1 or type 2),
  • moderate to severe kidney insufficiency (GFR < 60 mL/min/1.73 m2),
  • hyperkalemia (> 5 mMol/L) or
  • congestive heart failure who are hypotensive (see WARNINGS AND PRECAUTIONS, Dual blockade of the Renin-Angiotensin System (RAS) and Renal Impairment, and DRUG INTERACTIONS, Aliskiren-containing medicines and Angiotensin receptor blockers (ARBs) or other ACE inhibitors).
• Combination with angiotensin receptor blockers (ARBs) or other ACE inhibitors in patients with
  • diabetes with end organ damage,
  • moderate to severe kidney insufficiency (GFR < 60 mL/min/1.73m2),
  • hyperkalemia (> 5mMol/L) or
  • congestive heart failure who are hypotensive (see DRUG INTERACTIONS, Angiotensin receptor blockers (ARBs) or other ACE inhibitors).
• Patients with hereditary problems of galactose intolerance, glucose-galactose malabsorption or the Lapp lactase deficiency as ACCUPRIL contains lactose (see WARNINGS AND PRECAUTIONS, Sensitivity/Resistance).

Hypertension artérielle

La monothérapie par ACCUPRIL (chlorhydrate de quinapril) a fait l'objet d'une étude d'innocuité chez 2 005 sujets hypertendus, dont 313 personnes âgées, ayant participé à des essais cliniques contre placebo. Les effets indésirables n'ont pas été plus fréquents chez les personnes âgées que chez les autres sujets traités aux mêmes posologies quotidiennes. ACCUPRIL a aussi fait l'objet d'études d'innocuité à long terme chez plus de 1 100 patients traités pendant un an ou plus. Les effets indésirables ont été bénins et passagers.

L’effet indésirable le plus grave a été l'œdème angioneurotique (0,1 %). On a aussi signalé un cas d'insuffisance rénale, un cas d'agranulocytose et deux cas d'hyperazotémie légère chez des personnes souffrant d'insuffisance cardiaque congestive. Des infarctus du myocarde et des accidents vasculaires cérébraux sont survenus. Ils étaient peut-être secondaires à une hypotension excessive chez des patients à risque élevé (voir MISES EN GARDE ET PRÉCAUTIONS, Système cardiovasculaire, Hypotension).

Dans les essais cliniques contrôlés, les effets indésirables s'étant produits le plus fréquemment sont les suivants : céphalées (8,1 %), étourdissements (4,1 %), toux (3,2 %), fatigue (3,2 %), rhinite (3,2 %), nausées et/ou vomissements (2,3 %) et douleurs abdominales (2,0 %).

Les effets indésirables ont nécessité l'arrêt du traitement chez 4,7 % des sujets traités par ACCUPRIL dans ces essais contre placebo.

Insuffisance cardiaque congestive (ICC)

Sur les 1 108 sujets souffrant d'insuffisance cardiaque congestive, 605 (55 %) ont eu au moins un effet indésirable. Cinq cent vingt-cinq d'entre eux ont participé à une étude d'innocuité dans les essais cliniques contrôlés. Les fréquences des effets indésirables ont été semblables chez les deux sexes ainsi que chez les sujets âgés (> 65 ans) et les plus jeunes (< 65 ans).

Les effets ou manifestations indésirables non mortels les plus graves ont été les suivants : œdème angioneurotique (0,1 %), douleur thoracique d'origine inconnue (0,8 %), angine de poitrine (0,4 %), hypotension artérielle (0,1 %) et dysfonction rénale (voir MISES EN GARDE ET PRÉCAUTIONS, Fonction rénale, Insuffisance rénale). Des cas d'infarctus du myocarde et d'accident vasculaire cérébral ont été observés (voir MISES EN GARDE ET PRÉCAUTIONS, Système cardiovasculaire, Hypotension). De rares cas de pneumonie éosinophile ont été signalés. De rares cas d’hépatite ou d’insuffisance hépatique ont été signalés avec les autres inhibiteurs de l’ECA.

Dans les essais cliniques contrôlés, les effets indésirables les plus fréquents ont été les suivants : étourdissements (11,2 %), toux (7,6 %), douleur thoracique (6,5 %), dyspnée (5,5 %), fatigue (5,1 %) et nausées/vomissements (5,0 %).

Quarante et un (41) sujets (8,0 %) des essais cliniques contrôlés ont dû cesser le traitement à cause d’effets indésirables. L'hypotension (0,8 %) et la toux (0,8 %) ont constitué les principaux motifs d'abandon.

Le tableau 1 présente les effets indésirables observés pendant l'étude d'innocuité, chez ≥ 0,5 % de tous les sujets, les 2 005 sujets hypertendus traités par ACCUPRIL en monothérapie et les 525 sujets insuffisants cardiaques traités par ACCUPRIL en traitement adjuvant.

¹    ACCUPRIL monotherapy
²    ACCUPRIL as adjunctive therapy to diuretic and/or digitalis.

Les manifestations cliniques indésirables qui sont probablement, possiblement ou sûrement liées au traitement, ou dont la relation reste incertaine, signalées chez 0,5 % à 1,0 % au plus des patients traités par le quinapril (avec ou sans diurétique en concomitance), au cours d’essais cliniques comparatifs ou non, et les manifestations moins fréquentes observées au cours d’essais cliniques ou après la commercialisation du produit (indiquées par un astérisque [*]) sont les suivantes :

Hypertension artérielle

ACCUPRIL (chlorhydrate de quinapril) est indiqué pour le traitement de l'hypertension artérielle essentielle. Il est habituellement administré en association avec d'autres médicaments, en particulier des diurétiques thiazidiques.

L'efficacité et l'innocuité d'ACCUPRIL dans les cas d'hypertension rénovasculaire ne sont pas établies; l'emploi de ce médicament chez les patients souffrant de cette condition n'est donc pas recommandé.

Insuffisance cardiaque congestive

ACCUPRIL est indiqué dans le traitement de l'insuffisance cardiaque congestive à titre de traitement adjuvant aux diurétiques et/ou aux glucosides digitaliques.

La mise en route du traitement par ACCUPRIL doit être faite sous étroite surveillance médicale

Personnes âgées (> 65 ans)

Sur l’ensemble des patients qui ont participé aux études sur ACCUPRIL, 21 % étaient âgés de 65 ans ou plus. (Il n’y avait pas de différence entre les patients de plus de 65 ans et ceux de plus de 75 ans.) On n’a signalé aucune différence sur le plan de l’innocuité ou de l’efficacité entre ces sujets et les sujets plus jeunes, et les autres données ne mettent pas en lumière de différence entre la réponse des patients plus jeunes et celle des plus âgés sur le plan clinique. On ne peut toutefois pas exclure la possibilité d’une sensibilité accrue chez les sujets plus âgés.

Enfants (< 18 ans)

L'efficacité et l'innocuité d'ACCUPRIL n'ayant pas été établies chez les enfants, l'emploi du médicament n'est pas recommandé dans ce groupe d'âge.

ACCUPRIL (quinapril hydrochloride) tablets are supplied as follows:

ACCUPRIL 5 mg: Contains 5 mg quinapril per tablet. Brown, film-coated, elliptical tablets, debossed "PD 527" on one side and "5" on the other side. Bottles of 90 tablets.

ACCUPRIL 10 mg: Contains 10 mg quinapril per tablet. Brown, film-coated, triangular tablets, debossed "PD 530" on one side and "10" on the other side. Bottles of 90 tablets.

ACCUPRIL 20 mg: Contains 20 mg quinapril per tablet. Brown, film-coated, round tablets, debossed "PD 532" on one side and "20" on the other side. Bottles of 90 tablets.

ACCUPRIL 40 mg: Contains 40 mg quinapril per tablet. Brown, film-coated, elliptical tablets, debossed "PD 535" on one side and "40" on the other side. Bottles of 90 tablets.

Composition

ACCUPRIL tablets contain 5 mg, 10 mg, 20 mg or 40 mg quinapril per tablet (as the hydrochloride salt). Each tablet also contains candelilla wax, crospovidone, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, lactose, magnesium carbonate, magnesium stearate, polyethylene glycol, synthetic red iron oxide and titanium dioxide.

No data are available regarding overdosage with ACCUPRIL. The most likely clinical manifestation would be symptoms attributable to severe hypotension, which should be normally treated by intravenous volume expansion with 0.9% sodium chloride. Hemodialysis and peritoneal dialysis have little effect on the elimination of quinapril and quinaprilat.

Hypertension

ACCUPRIL (quinapril hydrochloride) monotherapy was evaluated for safety in 2005 hypertensive patients, including 313 elderly patients, enrolled in placebo-controlled clinical trials. There was no increase in the incidence of adverse events (AEs) in elderly patients given the same daily dosages. ACCUPRIL was evaluated for long-term safety in >1100 patients treated for ≥1 year. AEs were usually mild and transient in nature.
The most serious AE was angioedema (0.1%). Renal insufficiency (1 case), agranulocytosis (1 case) and mild azotemia (2 cases in CHF patients) have been reported. Myocardial infarction and cerebrovascular accident occurred, possibly secondary to excessive hypotension in high risk patients (see WARNINGS AND PRECAUTIONS, Cardiovascular, Hypotension).

The most frequent AEs in controlled clinical trials were headache (8.1%), dizziness (4.1%), cough (3.2%), fatigue (3.2%), rhinitis (3.2%), nausea and/or vomiting (2.3%), and abdominal pain (2.0%).

Discontinuation of therapy because of AEs was required in 4.7% of patients treated with ACCUPRIL in placebo-controlled trials.

Congestive Heart Failure (CHF)

Out of the 1108 patients with CHF, 605 (55%) experience ≥1 AE. In controlled clinical trials, 525 of these patients were evaluated for safety. The frequencies of AEs were similar for both sexes as well as for younger (< 65 years) and older (> 65 years) patients.

The most serious non-fatal AEs/reactions were angioedema (0.1%), chest pain of unknown origin (0.8%), angina pectoris (0.4%), hypotension (0.1%) and impaired renal function (see WARNINGS AND PRECAUTIONS, Renal, Renal Impairment). Myocardial infarct and cerebrovascular accident occurred (see WARNINGS AND PRECAUTIONS, Cardiovascular, Hypotension). Rare cases of eosinophilic pneumonitis have been reported. Hepatitis or hepatic failure have rarely been observed with other ACE inhibitors.

The most frequent AEs in controlled clinical trials were dizziness (11.2%), cough (7.6%), chest pain (6.5%), dyspnea (5.5%), fatigue (5.1%), and nausea/vomiting (5.0%).

Discontinuation due to AEs in controlled clinical trials was required for 41 (8.0%) patients. Hypotension (0.8%) and cough (0.8%) were the most common reasons for withdrawal.

AEs occurring in ≥ 0.5% of 2005 hypertensive patients treated with ACCUPRIL monotherapy and in 525 patients with CHF treated with ACCUPRIL as adjunctive therapy, in controlled clinical trials, are presented in the table below:

¹    ACCUPRIL monotherapy
²    ACCUPRIL as adjunctive therapy to diuretic and/or digitalis.

AEs occurring in <0.5% of patients with hypertension or CHF include:

Clinical adverse experiences probably, possibly, or definitely related, or of uncertain relationship to therapy occurring in 0.5% to < 1.0% of the patients treated with quinapril (with or without concomitant diuretic) in controlled or uncontrolled clinical trials and less frequent events seen in clinical trials or post-marketing experience (indicated by a *) included:

Hypertension

ACCUPRIL (quinapril hydrochloride) is indicated in the treatment of essential hypertension. It is usually administered in association with other drugs, particularly thiazide diuretics.

The safety and efficacy of ACCUPRIL in renovascular hypertension has not been established; therefore, use in this condition is not recommended.

Congestive Heart Failure

ACCUPRIL is indicated in the treatment of congestive heart failure as adjunctive therapy when added to diuretics and/or digitalis glycosides.
Treatment with ACCUPRIL should be initiated under close medical supervision.

Geriatrics (>65 years of age)

Of the total number of subjects in clinical studies of ACCUPRIL, 21% were ≥65 years old. (There was no distinction between patients >65 or >75 years.) No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience did not identify differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Pediatrics (<18 years of age)

The safety and effectiveness of ACCUPRIL in children have not been established, therefore use in this age group is not recommended.

Généralités

Œdème angioneurotique de la tête et du cou

Des cas d'œdème angioneurotique de la tête et du cou ont été signalés chez des sujets traités par ACCUPRIL. L'œdème angioneurotique avec atteinte laryngée peut être mortel. Lorsqu'un stridor laryngé ou un œdème angioneurotique de la face, de la langue ou de la glotte apparaissent, il faut cesser immédiatement l'administration d'ACCUPRIL, donner au patient les soins médicaux pertinents, conformément à la pratique médicale, et observer attentivement l'évolution de son état jusqu'à la disparition de l'œdème. Quand l'œdème se limite à la face et aux lèvres, il se résorbe, en général, spontanément sans traitement, bien que les antihistaminiques puissent atténuer les symptômes. Lorsque l'œdème atteint la langue, la glotte ou le larynx et risque d'obstruer les voies aériennes, on doit administrer sans délai des soins pertinents, notamment une injection sous-cutanée de 0,3 à 0,5 mL d'adrénaline diluée au 1/1000e, sans exclure d'autres mesures (voir EFFETS INDÉSIRABLES).

L'incidence d'œdème angioneurotique au cours du traitement par un inhibiteur de l'ECA s'est avérée plus élevée chez les sujets de race noire que chez ceux d'autres races.

Les patients qui prennent en concomitance un inhibiteur de la mTOR, comme le temsirolimus, ou un inhibiteur de la DPP-IV (dipeptidylpeptidase IV), comme la sitagliptine, peuvent être exposés à un plus grand risque d’œdème angioneurotique. La prudence s’impose lorsqu’on amorce un traitement par un inhibiteur de l’ECA chez des patients qui reçoivent déjà un inhibiteur de la mTOR ou un inhibiteur de la DPP-IV, ou vice versa (voir INTERACTIONS MÉDICAMENTEUSES).

Les patients ayant des antécédents d'œdème angioneurotique imputable ou non au traitement par inhibiteur de l'ECA risquent plus d'avoir un œdème angioneurotique lorsqu'ils sont traités par inhibiteur de l'ECA (voir CONTRE-INDICATIONS).

Œdème angioneurotique intestinal

Des cas d’œdème angioneurotique intestinal ont été signalés chez des patients traités par un inhibiteur de l’ECA. Ces patients se sont présentés avec des douleurs abdominales (avec ou sans diarrhée ou vomissements); certains n’avaient aucun antécédent d’œdème angioneurotique de la face, et leurs taux de C₁ estérase étaient normaux. L’œdème angioneurotique a été diagnostiqué à l’aide d’examens, entre autres par tomodensitométrie ou échographie abdominale, ou lors d’une intervention chirurgicale. Les symptômes ont disparu après l’arrêt du traitement par l’inhibiteur de l’ECA. L’œdème angioneurotique intestinal devrait faire partie du diagnostic différentiel chez les patients sous inhibiteur de l’ECA ayant des douleurs abdominales.

Système cardiovasculaire

Double inhibition du système rénine-angiotensine

Double inhibition du système rénine-angiotensine : Des données indiquent que l’administration concomitante d’un inhibiteur de l’ECA (comme ACCUPRIL) ou d’un agoniste des récepteurs de l’angiotensine et d’aliskirène augmente le risque d’hypotension, de syncope, d’accident vasculaire cérébral, d’hyperkaliémie et d’altérations de la fonction rénale, dont l’insuffisance rénale aiguë, chez les patients atteints de diabète (type 1 ou 2) et/ou d’insuffisance rénale modérée ou grave (filtration glomérulaire < 60 mL/min/1,73 m2). L’emploi d’ACCUPRIL en association avec des médicaments contenant de l’aliskirène est donc contre-indiqué chez ces patients (voir CONTRE-INDICATIONS).

De plus, l’administration concomitante d’un inhibiteur de l’ECA, y compris ACCUPRIL, et d’autres agents qui inhibent le système rénine-angiotensine, tels les agonistes des récepteurs de l’angiotensine et les médicaments contenant de l’aliskirène, est généralement déconseillée chez les autres patients. En effet, on a fait un rapprochement entre une telle association thérapeutique et une augmentation des cas graves d’hypotension, d’insuffisance rénale et d’hyperkaliémie. L’emploi de cette association doit se limiter à certains cas bien définis et s’accompagner d’une surveillance étroite de la fonction rénale et de la kaliémie (voir CONTRE-INDICATIONS).

Hypotension

Une hypotension symptomatique est présente parfois après l'administration d'ACCUPRIL, habituellement après la première ou la deuxième prise ou lorsqu'on augmente la dose. Cette réaction est plus susceptible de se produire en présence d'hypovolémie provoquée par un traitement diurétique, un régime hyposodé, une dialyse, la diarrhée ou des vomissements. Dans les cas de cardiopathie ischémique ou de maladie vasculaire cérébrale, une chute excessive de la tension artérielle risque de provoquer un infarctus du myocarde ou un accident vasculaire cérébral (voir EFFETS INDÉSIRABLES). À cause du risque de chute de tension chez ces patients, il faut commencer le traitement par ACCUPRIL avec étroite surveillance médicale (voir POSOLOGIE ET MODE D’ADMINISTRATION); il faut aussi suivre ces patients de près pendant les premières semaines de traitement et chaque fois qu'on augmente la dose d'ACCUPRIL. En présence d'insuffisance cardiaque congestive grave, accompagnée ou non d'insuffisance rénale, on observe parfois une réaction hypotensive excessive, pouvant s'accompagner d'oligurie et/ou d'hyperazotémie évolutive et, dans de rares cas, d'insuffisance rénale aiguë et/ou de mort.

Lorsqu'une hypotension se produit, le patient doit être placé en position couchée et, au besoin, recevoir par perfusion une solution intraveineuse de chlorure de sodium à 0,9 %. Une réaction hypotensive transitoire n'est pas une contre-indication à l'administration d'autres doses, généralement sans difficulté, une fois que la tension artérielle a augmenté grâce à l'expansion volumique. On doit toutefois considérer la possibilité d'administrer de plus faibles doses d'ACCUPRIL, de diminuer le traitement diurétique concomitant ou de prendre ces deux mesures à la fois.

Sténose valvulaire

Le risque particulier d'insuffisance coronarienne que pourraient courir les patients ayant une sténose de l'aorte et traités par des vasodilatateurs soulève des craintes au point de vue théorique, du fait que chez eux la postcharge ne diminue pas autant.

Système endocrinien et métabolisme

Hyperkaliémie et diurétiques d'épargne potassique

On a observé une élévation de la kaliémie (> 5,7 mmol/L) chez environ 2 % des patients traités par ACCUPRIL. Il s'agissait, dans la plupart des cas, d'une anomalie isolée et les valeurs sont revenues à la normale malgré la poursuite du traitement. L'hyperkaliémie a nécessité l'arrêt du traitement chez moins de 0,1 % des sujets hypertendus. Les facteurs de risque d'hyperkaliémie peuvent comprendre l'insuffisance rénale, le diabète sucré et l'emploi concomitant de médicaments pour le traitement d'une hypokaliémie (voir MISES EN GARDE ET PRÉCAUTIONS, Surveillance et épreuves de laboratoire, Hyperkaliémie, EFFETS INDÉSIRABLES, et INTERACTIONS MÉDICAMENTEUSES, Agents augmentant la kaliémie).

Hypoglycémie et diabète

Les inhibiteurs de l’ECA peuvent réduire la résistance à l’insuline et provoquer une hypoglycémie chez les diabétiques qui prennent de l’insuline ou des hypoglycémiants par voie orale; une surveillance étroite des patients diabétiques peut se révéler nécessaire.

Hématologie

Neutropénie et agranulocytose

Les inhibiteurs de l'ECA ont déjà causé une agranulocytose et une aplasie médullaire. Une agranulocytose a été observée pendant le traitement par ACCUPRIL chez un patient ayant déjà présenté une neutropénie au cours d'un traitement antérieur par le captopril. La surveillance périodique de la numération leucocytaire est donc à envisager, en particulier en présence de collagénose vasculaire et/ou de maladie rénale.

Fonction hépatique

Personnes souffrant d'insuffisance hépatique

Une hépatite (cytolytique et/ou cholestatique) et des élévations des taux d'enzymes hépatiques et/ou de bilirubine plasmatiques ont été observées pendant le traitement par inhibiteurs de l'ECA, chez des patients avec ou sans anomalies hépatiques préexistantes. Dans la plupart des cas, ces anomalies ont disparu après l'arrêt de l'administration du médicament.

Des cas d'élévation des taux d'enzymes hépatiques et/ou de bilirubine plasmatiques ont été signalés avec le traitement par ACCUPRIL (voir EFFETS INDÉSIRABLES). Lorsqu'un patient traité par ACCUPRIL présente des symptômes inexpliqués, surtout pendant les premières semaines ou les premiers mois de traitement, il est recommandé de procéder à la série complète d'épreuves fonctionnelles hépatiques et à toute autre exploration jugée nécessaire. Au besoin, l'arrêt du traitement par ACCUPRIL est à envisager.

Il n'y a pas eu suffisamment d'études effectuées chez des patients présentant une cirrhose et/ou des troubles fonctionnels hépatiques. Il convient de faire preuve de prudence avec l'emploi d'ACCUPRIL dans les cas d'anomalies hépatiques préexistantes. Chez de tels patients, il faut procéder à une exploration fonctionnelle hépatique avant l'administration du médicament et à une étroite surveillance de la réponse du patient et des effets métaboliques du traitement.

Il faut faire preuve de prudence lorsqu’on prescrit ACCUPRIL (quinapril) en association avec un diurétique à un patient atteint d’un dysfonctionnement hépatique ou d’une hépatopathie évolutive, puisque des modifications, même légères, de l’équilibre hydroélectrolytique peuvent provoquer un coma hépatique. La biotransformation du quinapril en quinaprilate dépend habituellement de l’estérase hépatique. La concentration plasmatique de quinaprilate diminue en présence de cirrhose alcoolique, en raison d’une diminution de la désestérification du quinapril.

Système immunitaire

Réactions anaphylactoïdes au cours de la dialyse

Des réactions anaphylactoïdes ont été rapportées chez les patients dont la dialyse est effectuée à travers des membranes à débit rapide (ex. polyacrylonitrile [PAN]) et suivant un traitement concomitant par un inhibiteur de l'ECA. La dialyse devrait être arrêtée immédiatement si des symptômes tels que des nausées, des crampes abdominales, des sensations de brûlure, un œdème angioneurotique, un essoufflement et une hypotension grave sont présents. Les antihistaminiques ne soulagent pas ces symptômes. Chez ces patients, il faudrait considérer l'utilisation d'une autre sorte de membrane pour la dialyse ou d'une autre catégorie d'antihypertenseurs.

Réactions anaphylactoïdes au cours de l'aphérèse des LDL

De rares cas de réactions anaphylactoïdes mettant la vie du patient en danger ont été rapportés lors de l'utilisation des inhibiteurs de l'ECA pendant l'aphérèse des lipoprotéines de basse densité au dextran-sulfate. Ces réactions ont pu être évitées en interrompant provisoirement l'utilisation de l'inhibiteur de l'ECA avant chaque aphérèse.

Réactions anaphylactoïdes au cours de la désensibilisation

Des cas isolés de réactions anaphylactoïdes prolongées mettant la vie du patient en danger ont été rapportés lors de l'utilisation d'inhibiteurs de l'ECA pendant le traitement de désensibilisation au venin des hyménoptères (abeilles, guêpes). Chez ces mêmes patients, ces réactions ont été évitées lorsque l'utilisation des inhibiteurs de l'ECA a été provisoirement interrompue pendant au moins 24 heures, mais sont réapparues avec la reprise malencontreuse du traitement par inhibiteur de l'ECA.

Réactions nitritoïdes causées par l’injection de sels d’or

Des réactions nitritoïdes (symptômes comprenant rougeur du visage, nausées, vomissements et hypotension symptomatique) ont été signalées en de rares occasions chez des patients traités en même temps par des sels d’or injectables (p. ex., aurothiomalate de sodium) et un inhibiteur de l’ECA, dont ACCUPRIL (voir INTERACTIONS MÉDICAMENTEUSES).

Système nerveux

Effets sur la capacité de conduire un véhicule et d’utiliser des machines

La capacité d’effectuer certaines activités, telles que l’utilisation de machines ou la conduite d’un véhicule, peut être réduite, particulièrement au début du traitement par le quinapril.

Considérations périopératoires

Chirurgie et anesthésie

Chez les sujets qui subissent une intervention chirurgicale importante ou pendant l'anesthésie au moyen d'agents qui entraînent une hypotension, ACCUPRIL bloque la formation d'angiotensine II secondaire à la libération compensatrice de rénine. Si une hypotension imputée à ce mécanisme est présente, on peut la corriger par expansion volumique.

Fonction rénale

Insuffisance rénale

L’administration concomitante d’un inhibiteur de l’ECA, y compris ACCUPRIL, ou d’un agoniste des récepteurs de l’angiotensine et d’un médicament contenant de l’aliskirène est contre-indiquée chez les patients atteints d’insuffisance rénale modérée ou grave (filtration glomérulaire < 60 mL/min/1,73 m²) (voir CONTRE-INDICATIONS et INTERACTIONS MÉDICAMENTEUSES, Médicaments contenant de l’aliskirène et Antagonistes des récepteurs de l’angiotensine ou autres inhibiteurs de l’ECA).

Par suite de l'inhibition du système rénine-angiotensine-aldostérone, les sujets susceptibles ont présenté des changements de leur fonction rénale. Chez les patients dont la fonction rénale peut dépendre de l'activité du système rénine-angiotensine-aldostérone, dont ceux ayant une sténose des deux artères rénales, une sténose unilatérale avec rein unique ou une insuffisance cardiaque congestive grave, le traitement par des agents risquant d'inhiber ce système a été associé à une oligurie, à une hyperazotémie évolutive et, dans de rares cas, à une insuffisance rénale aiguë et/ou à la mort. Chez les patients susceptibles, l'emploi concomitant d'un diurétique peut accroître davantage le risque (voir EFFETS INDÉSIRABLES et POSOLOGIE ET MODE D’ADMINISTRATION).

L'emploi d'ACCUPRIL doit comprendre une évaluation appropriée de la fonction rénale (voir EFFETS INDÉSIRABLES et POSOLOGIE ET MODE D’ADMINISTRATION).

Appareil respiratoire

Toux

Des cas de toux ont été signalés lors de la prise d’inhibiteurs de l’ECA, y compris de quinapril. Il s’agit d’une toux caractéristique, sèche et persistante, qui ne cède habituellement qu'après un arrêt du traitement ou une diminution de la dose d'ACCUPRIL. Il faut prendre en considération la toux causée par les inhibiteurs de l’ECA dans le diagnostic différentiel de ce trouble.

Sensibilité et résistance

Comme le lactose fait partie des ingrédients d’ACCUPRIL, ce dernier ne doit pas être administré aux patients atteints d’une maladie héréditaire comme une intolérance au galactose, un syndrome de malabsorption du glucose-galactose ou un déficit en lactase de Lapp (voir CONTRE- INDICATIONS).

Populations particulières

Femmes enceintes

Le quinapril est contre-indiqué pendant la grossesse (voir CONTRE-INDICATIONS et EFFETS INDÉSIRABLES). Administrés aux femmes enceintes, les inhibiteurs de l'ECA peuvent provoquer morbidité et mortalité fœtales et néonatales. Il y a eu plusieurs douzaines de cas signalés dans des articles parus à travers le monde. Lorsqu'une grossesse est décelée, il faut cesser dès que possible l'administration d'ACCUPRIL.

L'emploi des inhibiteurs de l'ECA pendant les deuxième et troisième trimestres de grossesse a été associé à des affections fœtales et néonatales, notamment à des cas d'hypotension artérielle, d'hypoplasie crânienne néonatale, d'anurie, d'insuffisance rénale réversible ou irréversible, et de mort. On a aussi signalé des cas d'oligoamnios probablement causé par la diminution de la fonction rénale du fœtus; dans ces circonstances, l'oligoamnios s'accompagnait parfois de contractures des membres du fœtus, de difformités craniofaciales et d'hypoplasie pulmonaire.

On a aussi signalé des naissances prématurées, des cas de persistance du canal artériel, d’autres malformations cardiaques structurelles ainsi que des anomalies neurologiques après une exposition à des inhibiteurs de l’ECA au cours du premier trimestre de grossesse.

Les nourrissons qui ont été exposés in utero aux inhibiteurs de l'ECA doivent faire l'objet d'une étroite surveillance, à la recherche d'hypotension, d'oligurie et d'hyperkaliémie. Si une oligurie se produit, on doit accorder une attention particulière au maintien de la tension artérielle et de l'irrigation rénale. Le recours à l'exsanguinotransfusion ou à la dialyse peut être nécessaire pour faire rétrocéder l'hypotension et/ou compenser l'insuffisance rénale; cependant, l’expérience restreinte qu’on possède de telles interventions n’a pas fait ressortir de bienfait clinique significatif.

En présence d’un oligoamnios, il peut être justifié de procéder à un examen de réactivité fœtale et/ou à un profil biophysique, selon le nombre de semaines de grossesse. Si la santé du fœtus reste préoccupante, on doit envisager de soumettre la patiente à une épreuve à l'ocytocine (EO). Médecins et patientes doivent cependant être conscients du fait que l'oligoamnios peut ne se manifester qu'après une atteinte irréversible du fœtus.

Données chez les animaux : Aucun effet fœtotoxique ou tératogène n'a été observé chez le rat à des doses atteignant 300 mg/kg par jour (180 fois la dose maximale recommandée en médecine humaine), malgré la maternotoxicité observée à la dose de 150 mg/kg par jour. On a constaté une diminution du poids des petits nés de mères traitées à des doses ≥ 25 mg/kg par jour, en période tardive de gestation et pendant la lactation. Le chlorhydrate de quinapril s'est révélé non tératogène chez la lapine; une maternotoxicité et une embryotoxicité ont cependant été observées chez quelques lapines traitées à la dose de 1 mg/kg par jour.

Aucun effet défavorable sur la fécondité ou sur la reproduction n'a été mis en évidence chez le rat à des doses ≤ 100 mg/kg par jour (60 fois la dose maximale recommandée en médecine humaine) (voir TOXICOLOGIE, Tableau 4).

Femmes qui allaitent

Des traces d’inhibiteurs de l’ECA ont été trouvées dans le lait maternel. L’emploi d’ACCUPRIL est donc contre-indiqué pendant l’allaitement (voir CONTRE-INDICATIONS).

Enfants (< 18 ans)

L'efficacité et l'innocuité d'ACCUPRIL n'ayant pas été établies chez les enfants, l'emploi du médicament n'est pas recommandé dans ce groupe d'âge.

Personnes âgées (> 65 ans)

Sur l’ensemble des patients qui ont participé aux études sur ACCUPRIL, 21 % étaient âgés de 65 ans ou plus. (Il n’y avait pas de différence entre les patients de plus de 65 ans et ceux de plus de 75 ans.) On n’a signalé aucune différence sur le plan de l’innocuité ou de l’efficacité entre ces sujets et les sujets plus jeunes, et les autres données ne mettent pas en lumière de différence entre la réponse des patients plus jeunes et celle des plus âgés sur le plan clinique. On ne peut toutefois pas exclure la possibilité d’une sensibilité accrue chez les sujets plus âgés.

On sait que ce médicament est éliminé par voie rénale, et le risque de réactions toxiques pourrait être plus élevé chez les patients présentant une altération de la fonction rénale. Étant donné que les patients plus âgés risquent davantage de présenter une telle altération, la dose du médicament devra être déterminée avec prudence, et il sera peut-être utile de surveiller la fonction rénale (voir EFFETS INDÉSIRABLES et POSOLOGIE ET MODE D’ADMINISTRATION).

Chez les patients plus âgés, on a observé une augmentation de l’aire sous la courbe concentration-temps et des pics sériques de quinaprilate, par rapport aux valeurs observées chez les sujets plus jeunes; cette augmentation semblait liée à une insuffisance rénale plutôt qu’à l’âge du sujet.

Surveillance et épreuves de laboratoire

Hématologie : Une surveillance périodique de la numération leucocytaire doit être envisagée, en particulier chez les patients atteints de collagénose vasculaire et/ou de maladie rénale (voir MISES EN GARDE ET PRÉCAUTIONS, Hématologie, Neutropénie et agranulocytose).
Hyperkaliémie : Les patients atteints d’insuffisance rénale ou de diabète ou qui prennent des médicaments pour traiter l’hypokaliémie peuvent présenter un risque accru d’hyperkaliémie. Le taux de potassium sérique doit être mesuré régulièrement (voir CONTRE-INDICATIONS, MISES EN GARDE ET PRÉCAUTIONS, Système endocrinien et métabolisme, Hyperkaliémie et diurétiques d’épargne potassique).
Créatinine et azote uréique : On a constaté des augmentations (> 1,25 fois la limite supérieure de la normale) des taux de créatinine et d'azote uréique dans le sang chez 2 % des sujets traités par ACCUPRIL en monothérapie. Ces augmentations étaient plus susceptibles de survenir chez les patients traités par ACCUPRIL et un diurétique que chez ceux traités seulement par ACCUPRIL (voir MISES EN GARDE ET PRÉCAUTIONS, Fonction rénale, Insuffisance rénale). Elles ont souvent rétrocédé avec la poursuite du traitement. Dans les essais cliniques contrôlés portant sur l'insuffisance cardiaque, on a observé des élévations des taux sanguins d'azote uréique et de la créatinine chez 11 % et 8 %, respectivement, des patients traités par ACCUPRIL. La plupart de ces patients prenaient aussi des diurétiques avec ou sans digitaliques. L’emploi d’ACCUPRIL doit comprendre une évaluation appropriée de la fonction rénale.
Foie : Des élévations des taux plasmatiques d’enzymes hépatiques et/ou de bilirubine ont été observées chez des patients traités par ACCUPRIL. Lorsqu’un patient traité par ACCUPRIL présente des symptômes inexpliqués, surtout pendant les premières semaines ou les premiers mois de traitement, on doit procéder à la série complète d’épreuves fonctionnelles hépatiques et à toute autre exploration jugée nécessaire. Au besoin, on doit envisager l’arrêt du traitement par ACCUPRIL. Dans les cas d’anomalies hépatiques préexistantes, il faut réaliser une exploration fonctionnelle hépatique avant l’administration du médicament et surveiller étroitement la réponse du patient et les effets métaboliques du traitement (voir MISES EN GARDE ET PRÉCAUTIONS, Fonction hépatique, Personnes souffrant d’insuffisance hépatique).