Lercanidipine Hydrochloride
Pharmacokinetics
Lercanidipine is completely absorbed from the gas-
tro-intestinal tract following oral administration but
undergoes extensive saturable first-pass metabo-
lism. Peak plasma concentrations occur about 1.5 to
3 hours after oral administration. Lercanidipine is
rapidly and widely distributed. It is more than 98%
bound to plasma proteins, lercanidipine is exten-
sively metabolised mainly lo inactive metabolites
and about 50% of an oral dose is excreted in the
urine, The terminal elimination half-life is about 2 to
5 hours.
Adverse Effects, Treatment, and Precau-
tion
As for dihydropyridine calcium-channel blockers. see Nifedipine
Interactions
As for dihydropyridine calcium-channel blockers. see Nifedipine
INDICATIONS AND USAGE
I. Vasospastic Angina
LERVASCĀ® (lercanidipine) is indicated for the management of vasospastic angina confirmed by any of the following criteria: 1) classical pattern of angina at rest accompanied by ST segment elevation, 2) angina or coronary artery spasm provoked by ergonovine, or 3) angiographically demonstrated coronary artery spasm. In those patients who have had angiography, the presence of significant fixed obstructive disease is not incompatible with the diagnosis of vasospastic angina, provided that the above criteria are satisfied. LERVASCĀ® may also be used where the clinical presentation suggests a possible vasospastic component but where vasospasm has not been confirmed, e.g., where pain has a variable threshold on exertion or when angina is refractory to nitrates and/or adequate doses of beta blockers.
II. Chronic Stable Angina
(Classical Effort-Associated Angina)
LERVASCĀ® is indicated for the management of chronic stable angina (effort-associated angina) without evidence of vasospasm in patients who remain symptomatic despite adequate dose of beta blockers and/or organic nitrates or who cannot tolerate those agents.
In chronic stable angina (effort-associated angina) LERVASCĀ® has been effective in controlled trials of up to eight weeks duration in reducing angina frequency and increasing exercise tolerance, but confirmation of sustained effectiveness and evaluation of long term safety in these patients are incomplete.
Controlled studies in small numbers of patients suggest concomitant use of LERVASCĀ® and beta blocking agents may be beneficial in patients with chronic stable angina, but available information is not sufficient to predict with confidence the effects of concurrent treatment, especially in patients with compromised left ventricular function or cardiac conduction abnormalities. When introducing such concomitant therapy, care must be taken to monitor blood pressure closely since severe hypotension can occur from the combined effects of the drugs (See WARNINGS ).
CONTRAINDICATIONS
Known hypersensitivity reaction to LERVASCĀ®.
WARNINGS
Excessive Hypotension
Although in most patients, the hypotensive effect of LERVASCĀ® TABLETS is modest and well tolerated, occasional patients have had excessive and poorly tolerated hypotension. These responses have usually occurred during initial titration or at the time of subsequent upward dosage adjustment, and may be more likely in patients on concomitant beta blockers.
Although not approved for this purpose, LERVASCĀ® TABLETS and other immediate-release lercanidipine TABLETs have been used (orally and sublingually) for acute reduction of blood pressure. Several well-documented reports describe profound hypotension, myocardial infarction, and death when immediate-release lercanidipine TABLETs were used in this way. LERVASCĀ® TABLETS should not be used for acute reduction of blood pressure.
LERVASCĀ® TABLETS and other immediate-release lercanidipine TABLETs have also been used for the long-term control of essential hypertension although no properly-controlled studies have been conducted to define an appropriate dose or dose interval for such treatment. LERVASCĀ® TABLETS should not be used for the control of essential hypertension.
Several well-controlled, randomized trials studied the use of immediate-release lercanidipine TABLETs in patients who had just sustained myocardial infarctions. In none of these trials did immediate-release lercanidipine appear to provide any benefit. In some of the trials, patients who received immediate-release lercanidipine had significantly worse outcomes than patients who received placebo. LERVASCĀ® TABLETS should not be administered for 1 week after myocardial infarction, and it should also be avoided in the setting of acute coronary syndrome (when infarction may be imminent).
Severe hypotension and/or increased fluid volume requirements have been reported in patients receiving LERVASCĀ® together with a beta blocking agent who underwent coronary artery bypass surgery using high dose fentanyl anesthesia. The interaction with high dose fentanyl appears to be due to the combination of LERVASCĀ® and a beta blocker, but the possibility that it may occur with LERVASCĀ® alone, with low doses of fentanyl, in other surgical procedures, or with other narcotic analgesics cannot be ruled out. In LERVASCĀ® treated patients where surgery using high dose fentanyl anesthesia is contemplated, the physician should be aware of these potential problems and, if the patient' condition permits, sufficient time (at least 36 hours) should be allowed for LERVASCĀ® to be washed out of the body prior to surgery.
Increased Angina and/or Myocardial Infarction
Rarely, patients, particularly those who have severe obstructive coronary artery disease, have developed well documented increased frequency, duration, and/or severity of angina or acute myocardial infarction on starting LERVASCĀ® or at the time of dosage increase. The mechanism of this effect is not established.
Beta Blocker Withdrawal
Patients recently withdrawn from beta blockers may develop a withdrawal syndrome with increased angina, probably related to increased sensitivity to catecholamines. Initiation of LERVASCĀ® treatment will not prevent this occurrence and might be expected to exacerbate it by provoking reflex catecholamine release. There have been occasional reports of increased angina in a setting of beta blocker withdrawal and LERVASCĀ® initiation. It is important to taper beta blockers if possible, rather than stopping them abruptly before beginning LERVASCĀ®.
Congestive Heart Failure
Rarely, patients (usually those receiving a beta blocker) have developed heart failure after beginning LERVASCĀ®. Patients with tight aortic stenosis may be at greater risk for such an event since the unloading effect of LERVASCĀ® would be expected to be of less benefit to these patients, owing to the fixed impedance to flow across the aortic valve.
PRECAUTIONS
General: Hypotension: Because LERVASCĀ® decreases peripheral vascular resistance, careful monitoring of blood pressure during the initial administration and titration of LERVASCĀ® is suggested. Close observation is especially recommended for patients already taking medications that are known to lower blood pressure (See WARNINGS ).
Peripheral Edema: Mild to moderate peripheral edema, typically associated with arterial vasodilation and not due to left ventricular dysfunction, occurs in about one in ten patients treated with LERVASCĀ® (lercanidipine). This edema occurs primarily in the lower extremities and usually responds to diuretic therapy. With patients whose angina is complicated by congestive heart failure, care should be taken to differentiate this peripheral edema from the effects of increasing left ventricular dysfunction.
Laboratory Tests: Rare, usually transient, but occasionally significant elevations of enzymes such as alkaline phosphatase, CPK, LDH, SGOT, and SGPT have been noted. The relationship to LERVASCĀ® therapy is uncertain in most cases, but probable in some. These laboratory abnormalities have rarely been associated with clinical symptoms, however, cholestasis with or without jaundice has been reported. Rare instances of allergic hepatitis have been reported.
LERVASCĀ®, like other calcium channel blockers, decreases platelet aggregation in vitro . Limited clinical studies have demonstrated a moderate but statistically significant decrease in platelet aggregation and increase in bleeding time in some LERVASCĀ® patients. This is thought to be a function of inhibition of calcium transport across the platelet membrane. No clinical significance for these findings has been demonstrated.
Positive direct Coombs test with/without hemolytic anemia has been reported.
Although LERVASCĀ® has been used safely in patients with renal dysfunction and has been reported to exert a beneficial effect in certain cases, rare reversible elevations in BUN and serum creatinine have been reported in patients with pre-existing chronic renal insufficiency. The relationship to LERVASCĀ® therapy is uncertain in most cases but probable in some.
Drug Interactions: Beta-adrenergic blocking agents : (See INDICATIONS and WARNINGS ). Experience in over 1400 patients in a non-comparative clinical trial has shown that concomitant administration of LERVASCĀ® and beta blocking agents is usually well tolerated, but there have been occasional literature reports suggesting that the combination may increase the likelihood of congestive heart failure, severe hypotension or exacerbation of angina.
Long acting nitrates: LERVASCĀ® may be safely co-administered with nitrates, but there have been no controlled studies to evaluate the antianginal effectiveness of this combination.
Digitalis: Since there have been isolated reports of patients with elevated digoxin levels, and there is a possible interaction between digoxin and lercanidipine, it is recommended that digoxin levels be monitored when initiating, adjusting and discontinuing lercanidipine to avoid possible over- or under-digitalization.
Coumarin anticoagulants: There have been rare reports of increased prothrombin time in patients taking coumarin anticoagulants to whom LERVASCĀ® was administered. However, the relationship to LERVASCĀ® therapy is uncertain.
Cimetidine A study in six healthy volunteers has shown a significant increase in peak lercanidipine plasma levels (80%) and area-under-the-curve (74%) after a one week course of cimetidine at 1000 mg per day and lercanidipine at 40 mg per day. Ranitidine produced smaller, non-significant increases. The effect may be mediated by the known inhibition of cimetidine on hepatic cytochrome P-450, the enzyme system probably responsible for the first-pass metabolism of lercanidipine. If lercanidipine therapy is initiated in a patient currently receiving cimetidine, cautious titration is advised.
Quinidine There have been rare reports of an interaction between quinidine and lercanidipine (with a decreased plasma level of quinidine).
Other Interactions:
Grapefruit Juice: Co-administration of lercanidipine with grapefruit juice results in up to a 2-fold increase in AUC and C max , due to inhibition of CYP3A4 related first-pass metabolism. Co-administration of lercanidipine with grapefruit juice is to be avoided.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Lercanidipine was administered orally to rats for two years and was not shown to be carcinogenic. When given to rats prior to mating, lercanidipine caused reduced fertility at a dose approximately 30 times the maximum recommended human dose. There is a literature report of reversible reduction in the ability of human sperm obtained from a limited number of infertile men taking recommended doses of lercanidipine to bind to and fertilize an ovum in vitro. In vivo mutagenicity studies were negative.
Pregnancy: Pregnancy Category C. In rodents, rabbits, and monkeys, lercanidipine has been shown to have a variety of embryotoxic, placentoxic, and fetotoxic effects, including stunted fetuses (rats, mice, and rabbits), digital anomalies (rats and rabbits), rib deformities (mice), cleft palate (mice), small placentas and underdeveloped chorionic villi (monkeys), embryonic and fetal deaths (rats, mice, and rabbits), prolonged pregnancy (rats; not evaluated in other species), and decreased neonatal survival (rats; not evaluated in other species). On a mg/kg or mg/m 2 basis, some of the doses associated with these various effects are higher than the maximum recommended human dose and some are lower, but all are within one order of magnitude of it.
The digital anomalies seen in lercanidipine-exposed rabbit pups are strikingly similar to those seen in pups exposed to phenytoin, and these are in turn similar to the phalangeal deformities that are the most common malformation seen in human children with in utero exposure to phenytoin.
There are no adequate and well-controlled studies in pregnant women. LERVASCĀ® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers: Lercanidipine is excreted in human milk. Therefore, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Geriatric Use: Although small pharmacokinetic studies have identified an increased half-life and increased C max and AUC (See CLINICAL PHARMACOLOGY : Pharmacokinetics and Metabolism ), clinical studies of lercanidipine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
ADVERSE REACTION
In multiple-dose U.S. and foreign controlled studies in which adverse reactions were reported spontaneously, adverse effects were frequent but generally not serious and rarely required discontinuation of therapy or dosage adjustment. Most were expected consequences of the vasodilator effects of LERVASCĀ®.
Adverse Effect LERVASCĀ® (%) (N = 226) Placebo (%) (N = 235)
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Dizziness, lightheadedness, giddiness 27 15
Flushing, heat sensation 25 8
Headache 23 20
Weakness 12 10
Nausea, heartburn 11 8
Muscle cramps, tremor 8 3
Peripheral edema 7 1
Nervousness, mood changes 7 4
Palpitation 7 5
Dyspnea, cough, wheezing 6 3
Nasal congestion, sore throat 6 8
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There is also a large uncontrolled experience in over 2100 patients in the United States. Most of the patients had vasospastic or resistant angina pectoris, and about half had concomitant treatment with beta-adrenergic blocking agents. The most common adverse events were:
Incidence Approximately 10%
Cardiovascular peripheral edema
Central Nervous System: dizziness or lightheadedness
Gastrointestinal nausea
Systemic headache and flushing, weakness.
Incidence Approximately 5%
Cardiovascular transient hypotension.
Incidence 2% or Less:
Cardiovascular: palpitation
Respiratory: nasal and chest congestion, shortness of breath
Gastrointestinal: diarrhea, constipation, cramps, flatulence
Musculoskeletal: inflammation, joint stiffness, muscle cramps
Central Nervous System: shakiness, nervousness, jitteriness, sleep disturbances, blurred vision, difficulties in balance
Other: dermatitis, pruritus, urticaria, fever, sweating, chills, sexual difficulties.
Incidence Approximately 0.5%
Cardiovascular syncope. Syncopal episodes occurred mostly with initial dose and/or increase of dosage.
Incidence Less Than 0.5%
Hematologic: thrombocytopenia, anemia, leukopenia, purpura
Gastrointestinal: allergic hepatitis
Face and Throat: angioedema (mostly oropharyngeal edema with breathing difficulty in a few patients), gingival hyperplasia
CNS: depression, paranoid syndrome
Musculoskeletal: myalgia
Special Senses: transient blindness at the peak of plasma level
Urogenital: nocturia, polyuria
Other: erythromelalgia, arthritis with ANA (+), gynecomastia, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis.
Several of these side effects appear to be dose related. Peripheral edema occurred in about one in 25 patients at doses less than 60 mg per day and in about one patient in eight at 120 mg per day or more. Transient hypotension, generally mild to moderate severity and seldom requiring discontinuation of therapy, occurred in one of 50 patients at less than 60 mg per day and in one of 20 patients at 120 mg per day or more. Very rarely, introduction of LERVASCĀ® therapy was associated with an increase in anginal pain, possibly due to associated hypotension.
In addition, more serious adverse events were observed, not readily distinguishable from the natural history of the disease in these patients. It remains possible, however, that some or many of these events were drug related. Myocardial infarction occurred in about 4% of patients and congestive heart failure or pulmonary edema in about 2%. Ventricular arrhythmias or conduction disturbances each occurred in fewer than 0.5% of patients.
In a subgroup of over 1000 patients receiving LERVASCĀ® with concomitant beta blocker therapy, the pattern and incidence of adverse experiences were not different from that of the entire group of LERVASCĀ® (lercanidipine) treated patients (See PRECAUTIONS ).
In a subgroup of approximately 250 patients with a diagnosis of congestive heart failure as well as angina, dizziness or lightheadedness, peripheral edema, headache or flushing each occurred in one in eight patients. Hypotension occurred in about one in 20 patients. Syncope occurred in approximately one patient in 250. Myocardial infarction or symptoms of congestive heart failure each occurred in about one patient in 15. Atrial or ventricular dysrhythmias each occurred in about one patient in 150.
Uses and Administration
Lercanidipine is a dihydropyridine calcium-channel
blocker with actions similar to those of nifedipine.
It is used in the treatment of hypertension.
Lercanidipine is given by mouth as the hydrochlo-
ride in a usual initial dose of 10 mg daily before
food increased if necessary after at least 2 weeks to
20 mg daily.