替米沙坦氨氯地平说明书
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
TWYNSTA safely and effectively. See full prescribing information for TWYNSTA.
TWYNSTA? (telmisartan/amlodipine) Tablets
Initial U.S. Approval: 2009
WARNING: AVOID USE IN PREGNANCY
See full prescribing information for complete boxed warning.
When pregnancy is detected, discontinue TWYNSTA as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury
and even death to the developing fetus (5.1)
----------------------------RECENT MAJOR CHANGES-------------------------- Contraindications
(4)
2/2011 ----------------------------INDICATIONS AND USAGE--------------------------- ?TWYNSTA is an angiotensin II receptor blocker (ARB) and a
dihydropyridine calcium channel blocker (DHP-CCB) combination
product indicated for the treatment of hypertension alone or with other
antihypertensive agents (1)
?TWYNSTA tablets are indicated as initial therapy in patients likely to need multiple antihypertensive agents to achieve their blood pressure
goals (1)
----------------------DOSAGE AND ADMINISTRATION----------------------- ?Substitute TWYNSTA for its individually titrated components for patients on amlodipine and telmisartan. TWYNSTA may also be given
with increased amounts of amlodipine, telmisartan, or both, as needed.
(2.2, 2.3)
?Use TWYNSTA tablets to provide additional blood pressure lowering for patients not adequately controlled with amlodipine (or another
dihydropyridine calcium channel blocker) alone or with telmisartan (or
another angiotensin receptor blocker) alone (2.3)
?Dosage may be increased after at least 2 weeks to a maximum dose of 80/10 mg once daily, usually by increasing one component at a time but
both components can be raised to achieve more rapid control (2.1, 2.2) ?Majority of antihypertensive effect is attained within 2 weeks (2.1)
?Initiate with 40/5 mg or 80/5 mg once daily (2.4)
?Switch patients who experience dose-limiting adverse reactions on amlodipine to TWYNSTA tablets containing a lower dose of that
component (2.3) ---------------------DOSAGE FORMS AND STRENGTHS---------------------- ?Tablets: 40/5 mg, 40/10 mg, 80/5 mg, 80/10 mg (3)
-------------------------------CONTRAINDICATIONS------------------------------ ?Known hypersensitivity (e.g., anaphylaxis or angioedema) to
telmisartan, amlodipine or any other component of this product (4)
-----------------------WARNINGS AND PRECAUTIONS------------------------ ?Avoid fetal or neonatal exposure (5.1)
?Hypotension: Correct any volume or salt depletion before initiating therapy. Observe for signs and symptoms of hypotension. (5.2)
?Titrate slowly in patients with hepatic (5.4) or severe renal impairment
(5.5)
?Heart failure: Monitor for worsening (5.8)
?Avoid concomitant use of an ACE inhibitor and angiotensin receptor blocker (5.6)
?Myocardial infarction: Uncommonly, initiating a CCB in patients with severe obstructive coronary artery disease may precipitate myocardial
infarction or increased angina (5.7)
------------------------------ADVERSE REACTIONS------------------------------- ?In the placebo-controlled factorial design study, the most common reasons for discontinuation of therapy with TWYNSTA tablets were
peripheral edema, dizziness, and hypotension, each leading to
discontinuation of ≤0.5% of TWYNSTA-treated patients. Adverse
reactions that occurred at a ≥2% higher incidence on TWYNSTA tablets
than placebo were peripheral edema (4.8% vs 0%), dizziness (3.0% vs
2.2%), and back pain (2.2% vs 0%). (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at (800) 542-6257 or (800) 459-9906
TTY, or FDA at 1-800-FDA-1088 or https://www.docsj.com/doc/5510905842.html,/medwatch.
------------------------------DRUG INTERACTIONS-------------------------------?NSAIDS: Increased risk of renal impairment and loss of anti-
hypertensive effect (7)
-----------------------USE IN SPECIFIC POPULATIONS------------------------ ?Patients ≥75 years of age or hepatically impaired patients: Start with amlodipine or add amlodipine 2.5 mg to telmisartan (2.5, 8.5, 8.6)?Nursing Mothers: Choose to discontinue nursing or drug (8.3)
See 17 for PATIENT COUNSELING INFORMATION and FDA-
Approved patient labeling.
Revised:
6/2011
_______________________________________________________________________________________________________________________________________
FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: AVOID USE IN PREGNANCY
1INDICATIONS AND USAGE
2DOSAGE AND ADMINISTRATION
2.1General Considerations
2.2Replacement Therapy
2.3Add-on Therapy for Patients with Hypertension Not Adequately
Controlled on Antihypertensive Monotherapy
2.4Initial Therapy
2.5Dosing in Specific Populations
3DOSAGE FORMS AND STRENGTHS
4CONTRAINDICATIONS
5WARNINGS AND PRECAUTIONS
5.1Fetal/Neonatal Morbidity and Mortality
5.2Hypotension
5.3Hyperkalemia
5.4Patients with Impaired Hepatic Function
5.5Renal Function Impairment
5.6Dual Blockade of the Renin-Angiotensin-Aldosterone System
5.7Risk of Myocardial Infarction or Increased Angina
5.8Heart Failure
6ADVERSE REACTIONS
6.1Clinical Trials Experience
6.2Postmarketing Experience
7DRUG INTERACTIONS
7.1Drug Interactions with TWYNSTA Tablets
7.2Drug Interactions with Telmisartan
7.3Drug Interactions with Amlodipine
8USE IN SPECIFIC POPULATIONS
8.1Pregnancy
8.3Nursing Mothers
8.4Pediatric Use
8.5Geriatric Use
8.6Hepatic Insufficiency
8.7Race
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis,
Mutagenesis, Impairment of Fertility
13.3 Developmental
Toxicity
14 CLINICAL STUDIES
14.1 TWYNSTA Tablets
14.2 Telmisartan
14.3 Amlodipine
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
17.1 Pregnancy
17.2 Potential Interference with Mental Alertness, Motor Performance,
or Visual Acuity
*Sections or subsections omitted from the full prescribing information are not listed.
FULL PRESCRIBING INFORMATION
WARNING: AVOID USE IN PREGNANCY
When used in pregnancy, drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus. When pregnancy is detected, TWYNSTA tablets should be discontinued as soon as possible. See Warnings and Precautions (5.1).
1 INDICATIONS AND USAGE
TWYNSTA (telmisartan/amlodipine) tablets are indicated for the treatment of hypertension, alone or with other antihypertensive agents.
TWYNSTA tablets may also be used as initial therapy in patients who are likely to need multiple drugs to achieve their blood pressure goals.
Base the choice of TWYNSTA tablets as initial therapy for hypertension on an assessment of potential benefits and risks including whether the patient is likely to tolerate the starting dose of TWYNSTA tablets.
Patients with moderate or severe hypertension are at relatively high risk for cardiovascular events (such as strokes, heart attacks, and heart failure), kidney failure, and vision problems, so prompt treatment is clinically relevant. Consider the patient's baseline blood pressure, the target goal, and the incremental likelihood of achieving goal with a combination compared with monotherapy when deciding whether to use TWYNSTA tablets as initial therapy. Individual blood pressure goals may vary based upon the patient’s risk.
Data from an 8-week, placebo-controlled, multidose, factorial trial provide estimates of the probability of reaching a blood pressure goal with TWYNSTA compared to
telmisartan or amlodipine monotherapy and placebo [see Clinical Studies (14.1)].
The figures below provide estimates of the likelihood of achieving systolic and diastolic blood pressure control with TWYNSTA 80/10 mg tablets, based upon baseline systolic or diastolic blood pressure. The curve of each treatment group was estimated by logistic regression modeling. The estimated likelihood at the right tail of each curve is less reliable due to small numbers of subjects with high baseline blood pressures.
Treatment
% S B P < 140 m m H g
Baseline SBP (mmHg)
Treatment
% S B P < 130 m m H
g
Baseline SBP (mmHg)
Figure 1a: Probability of Achieving Systolic Blood Pressure <140 mmHg at Week 8 Figure 1b: Probability of Achieving Systolic Blood Pressure <130 mmHg at Week 8
Treatment
% D B P < 90 m m H g
Baseline DBP (mmHg)
Treatment
% D B P < 80 m m H g
Baseline DBP (mmHg)
Figure 2a: Probability of Achieving Diastolic Blood Pressure <90 mmHg at Week 8 Figure 2b: Probability of Achieving Diastolic Blood Pressure <80 mmHg at Week 8
The figures above provide an approximation of the likelihood of reaching a targeted blood pressure goal at 8 weeks. For example, a patient with a baseline blood pressure of 160/110 mmHg has about a 16% likelihood of achieving a goal of <140 mmHg (systolic) and 16% likelihood of achieving <90 mmHg (diastolic) on placebo. The likelihood of achieving these same goals on telmisartan is about 46% (systolic) and 26% (diastolic). The likelihood of achieving these same goals on amlodipine is about 69% (systolic) and 22% (diastolic). These likelihoods rise to 79% for systolic and 55% for diastolic with TWYNSTA. 2 DOSAGE AND ADMINISTRATION 2.1 General Considerations
Telmisartan is an effective treatment of hypertension in once daily doses of 20-80 mg while amlodipine is effective in doses of 2.5-10 mg.
Dosage must be individualized and may be increased after at least 2 weeks. Most of the antihypertensive effect is apparent within 2 weeks and maximal reduction is generally attained after 4 weeks. The maximum recommended dose of TWYNSTA tablets is 80/10 mg once daily.
The adverse reactions of telmisartan are uncommon and independent of dose; those of amlodipine are a mixture of dose-dependent phenomena (primarily peripheral edema) and dose-independent phenomena, the former much more common than the latter [see Adverse Reactions (6.1)].
TWYNSTA may be taken with or without food.
2.2 Replacement Therapy
Patients receiving amlodipine and telmisartan from separate tablets may instead receive TWYNSTA tablets containing the same component doses once daily. When substituting for individual components, increase the dose of TWYNSTA if blood pressure control has not been satisfactory.
2.3 Add-on Therapy for Patients with Hypertension Not Adequately Controlled on Antihypertensive Monotherapy
TWYNSTA tablets may be used to provide additional blood pressure lowering for patients not adequately controlled with amlodipine (or another dihydropyridine calcium channel blocker) alone or with telmisartan (or another angiotensin receptor blocker) alone.
Patients treated with 10 mg amlodipine who experience any dose-limiting adverse reactions such as edema, may be switched to TWYNSTA 40/5 mg tablets once daily, reducing the dose of amlodipine without reducing the overall expected antihypertensive response [see Adverse Reactions (6.1)].
2.4 Initial Therapy
A patient may be initiated on TWYNSTA tablets if it is unlikely that control of blood pressure would be achieved with a single agent. The usual starting dose of TWYNSTA is 40/5 mg once daily. Patients requiring larger blood pressure reductions may be started on TWYNSTA 80/5 mg once daily.
Initial therapy with TWYNSTA is not recommended in patients ≥75 years old or with hepatic impairment [see Dosage and Administration (2.5), Warnings and Precautions (5.4), and Use in Specific Populations (8.5, 8.6)].
Correct imbalances of intravascular volume- or salt-depletion, before initiating therapy with TWYNSTA tablets [see Warnings and Precautions (5.2)].
2.5 Dosing in Specific Populations
Renal Impairment
No initial dosage adjustment is required for patients with mild or moderate renal impairment. Titrate slowly in patients with severe renal impairment.
Hepatic Impairment
In most patients, initiate amlodipine therapy at 2.5 mg. Titrate slowly in patients with hepatic impairment.
Patients 75 Years of Age and Older
In most patients, initiate amlodipine therapy at 2.5 mg. Titrate slowly in patients 75 years of age and older.
3 DOSAGE FORMS AND STRENGTHS
TWYNSTA tablets are formulated for oral administration in the following strength combinations:
40/5 mg 40/10 mg 80/5 mg 80/10 mg
telmisartan 40 40 80 80
amlodipine equivalent 5 10 5 10
The telmisartan/amlodipine non-scored, multilayer tablets are of oval, biconvex shape. Tablets are white to off-white on one side and blue on the other side. The white side is debossed with the BOEHRINGER INGELHEIM symbol and with either A1, A2, A3, or A4 for the 40/5 mg, 40/10 mg, 80/5 mg, and 80/10 mg strengths, respectively.
4 CONTRAINDICATIONS
TWYNSTA tablets are contraindicated in patients with known hypersensitivity (e.g., anaphylaxis or angioedema) to telmisartan, amlodipine, or any other component of this product [see Adverse Reactions (6.2)].
PRECAUTIONS
5 WARNINGS
AND
5.1 Fetal/Neonatal Morbidity and Mortality
Telmisartan
Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature in patients who were taking angiotensin converting enzyme inhibitors. When pregnancy is detected, discontinue TWYNSTA tablets as soon as possible [see Boxed Warning].
The use of drugs that act directly on the renin-angiotensin system 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, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug.
These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. Inform mothers whose embryos and fetuses are exposed to an angiotensin II receptor antagonist only during the first trimester that most reports of fetal toxicity have been associated with second or third trimester exposure. Nonetheless, when patients become pregnant or are considering pregnancy, physicians should have the patient discontinue the use of TWYNSTA tablets as soon as possible.
Rarely (probably less often than once in every thousand pregnancies), no alternative to an angiotensin II receptor antagonist will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intra-amniotic environment.
If oligohydramnios is observed, TWYNSTA tablets should be discontinued unless they are considered life-saving for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.
Infants with histories of in utero exposure to an angiotensin II receptor antagonist 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 disordered renal function.
5.2 Hypotension
Telmisartan
In patients with an activated renin-angiotensin system, such as volume- or salt-depleted patients (e.g., those being treated with high doses of diuretics), symptomatic hypotension may occur after initiation of therapy with TWYNSTA tablets. Either correct this condition prior to administration of TWYNSTA tablets, or start treatment under close medical supervision with a reduced dose.
If hypotension does occur, place the patient in the supine position and, if necessary, give an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.
Amlodipine
Since the vasodilation induced by amlodipine is gradual in onset, acute hypotension has rarely been reported after oral administration. Nonetheless, observe patients with severe aortic stenosis closely when administering amlodipine, as one should with any vasodilator.
5.3 Hyperkalemia
Telmisartan
Hyperkalemia may occur in patients on ARBs, particularly in patients with advanced renal impairment, heart failure, on renal replacement therapy, or on potassium supplements, potassium-sparing diuretics, potassium-containing salt substitutes or other drugs that increase potassium levels. Consider periodic determinations of serum electrolytes to detect possible electrolyte imbalances, particularly in patients at risk.
5.4 Patients with Impaired Hepatic Function
Telmisartan
As the majority of telmisartan is eliminated by biliary excretion, patients with biliary obstructive disorders or hepatic insufficiency can be expected to have reduced clearance. Initiate telmisartan at low doses and titrate slowly in these patients [see Dosage and Administration (2.5), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].
Amlodipine
Amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t1/2) is 56 hours in patients with impaired hepatic function. Since patients with hepatic impairment have decreased clearance of amlodipine, start amlodipine or add amlodipine at 2.5 mg in patients with hepatic impairment. The lowest dose of TWYNSTA is 40/5 mg; therefore, initial therapy with TWYNSTA tablets is not recommended in hepatically impaired patients [see Use in Specific Populations (8.6)].
5.5 Renal Function Impairment
Telmisartan
As a consequence of inhibiting the renin-angiotensin-aldosterone system, anticipate changes in renal function in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure or renal dysfunction), treatment with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. Similar results may be anticipated in patients treated with telmisartan [see Clinical Pharmacology (12.3)].
In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen were observed. There has been no long term use of telmisartan in patients with unilateral or bilateral renal artery stenosis, but anticipate an effect similar to that seen with ACE inhibitors.
5.6 Dual Blockade of the Renin-Angiotensin-Aldosterone System
Telmisartan
As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function (including acute renal failure) have been reported. Dual blockade of the renin-angiotensin-aldosterone system (e.g., by adding an ACE-inhibitor to an angiotensin II receptor antagonist) should include close monitoring of renal function. The ONTARGET trial enrolled 25,620 patients ≥55 years old with atherosclerotic disease or diabetes with end-organ damage, randomized them to telmisartan only, ramipril only, or the combination, and followed them for a median of 56 months. Patients receiving the combination of telmisartan and ramipril did not obtain any additional benefit compared to monotherapy, but experienced an increased incidence of renal dysfunction (e.g., acute renal failure) compared with groups receiving telmisartan alone or ramipril alone. Concomitant use of telmisartan and ramipril is not recommended.
5.7 Risk of Myocardial Infarction or Increased Angina
Amlodipine
Uncommonly, patients, particularly those with severe obstructive coronary artery disease, have developed documented increased frequency, duration or severity of angina or acute myocardial infarction on starting calcium channel blocker therapy or at the time of dosage increase. The mechanism of this effect has not been elucidated.
5.8 Heart Failure
Amlodipine
Closely monitor patients with heart failure.
Amlodipine (5-10 mg per day) has been studied in a placebo-controlled trial of 1153 patients with NYHA Class III or IV heart failure on stable doses of ACE inhibitor, digoxin, and diuretics. Follow-up was at least 6 months, with a mean of about 14 months. There was no overall adverse effect on survival or cardiac morbidity (as defined by life-threatening arrhythmia, acute myocardial infarction, or hospitalization for worsened heart failure). Amlodipine has been compared to placebo in four 8-12 week studies of patients with NYHA class II/III heart failure, involving a total of 697 patients. In these studies, there was no evidence of worsening of heart failure based on measures of exercise tolerance, NYHA classification, symptoms, or LVEF. In the PRAISE-2 study, 1654 patients with NYHA class III (80%) or IV (20%) heart failure without evidence of underlying ischemic disease, on stable doses of ACE inhibitor (99%), digitalis (99%), and diuretics (99%) were randomized 1:1 to receive placebo or amlodipine and followed for a mean of 33 months. While there was no statistically significant difference between amlodipine and placebo in the
primary endpoint of all cause mortality (95% confidence limits from 8% reduction to 29% increase on amlodipine), there were more reports of pulmonary edema in the patients on amlodipine.
6 ADVERSE REACTIONS 6.1 Clinical Trials Experience
Because clinical studies are conducted under widely varying conditions, adverse reactions rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
TWYNSTA Tablets
The concomitant use of telmisartan and amlodipine has been evaluated for safety in more than 3700 patients with hypertension; approximately 1900 of these patients were exposed for at least 6 months and over 160 of these patients were exposed for at least one year. Adverse reactions have generally been mild and transient in nature and have only infrequently required discontinuation of therapy.
In the placebo-controlled factorial design study, the population treated with a telmisartan and amlodipine combination had a mean age of 53 years and included approximately 50% males, 79% were Caucasian, 17% Blacks, and 4% Asians. Patients received doses ranging from 20/2.5 mg to 80/10 mg orally, once daily.
The frequency of adverse reactions was not related to gender, age, or race.
The adverse reactions that occurred in the placebo-controlled factorial design trial in ≥2% of patients treated with TWYNSTA and at a higher incidence in TWYNSTA-treated patients (n=789) than placebo-treated patients (n=46) were peripheral edema (4.8% vs 0%), dizziness (3.0% vs 2.2%), and back pain (2.2% vs 0%). Edema (other than peripheral edema), hypotension, and syncope were reported in <2% of patients treated with TWYNSTA tablets.
In the placebo-controlled factorial design trial, discontinuation due to adverse events occurred in 2.2% of all treatment cells of patients in the telmisartan/amlodipine-treated patients and in 4.3% in the placebo-treated group. The most common reasons for discontinuation of therapy with TWYNSTA tablets were peripheral edema, dizziness, and hypotension (each ≤0.5%).
Peripheral edema is a known, dose-dependent adverse reaction of amlodipine, but not of telmisartan. In the factorial design study, the incidence of peripheral edema during the 8 week, randomized, double-blind treatment period was highest with amlodipine 10 mg monotherapy. The incidence was notably lower when telmisartan was used in combination with amlodipine 10 mg.
Table 1: Incidence of Peripheral Edema During the 8 Week Treatment Period Telmisartan Placebo 40 mg 80 mg
A m l o d i p i n e
Placebo
0% 0.8% 0.7% 5 mg
0.7% 1.4% 2.1% 10 mg 17.8% 6.2% 11.3% Telmisartan
Telmisartan has been evaluated for safety in more than 3700 patients, including 1900 treated for over 6 months and more than 1300 for over one year. Adverse experiences have generally been mild and transient in nature and have only infrequently required discontinuation of therapy.
In placebo-controlled trials involving 1041 patients treated with various doses of telmisartan (20-160 mg) monotherapy for up to 12 weeks, an overall incidence of adverse events was similar to the patients treated with placebo.
Adverse events occurring at an incidence of ≥1% in patients treated with telmisartan and at a greater rate than in patients treated with placebo, irrespective of their causal association, are presented in Table 2.
Table 2: Adverse Events Occurring at an Incidence of ≥1% in Patients Treated with Telmisartan and at a Greater Rate than Patients Treated with Placebo
Telmisartan n=1455 % Placebo
n=380 %
Upper respiratory tract infection 7 6 Back pain 3 1 Sinusitis 3 2 Diarrhea 3 2 Pharyngitis 1 0
In addition to the adverse events in the table, the following events occurred at a rate of ≥1% but were at least as frequent in the placebo group: influenza-like
symptoms, dyspepsia, myalgia, urinary tract infection, abdominal pain, headache, dizziness, pain, fatigue, coughing, hypertension, chest pain, nausea, and peripheral edema. Discontinuation of therapy because of adverse events was required in 2.8% of 1455 patients treated with telmisartan tablets and 6.1% of 380 placebo patients in placebo-controlled clinical trials.
The incidence of adverse events was not dose-related and did not correlate with gender, age, or race of patients.
The incidence of cough occurring with telmisartan in 6 placebo-controlled trials was identical to that noted for placebo-treated patients (1.6%).
In addition to those listed above, adverse events that occurred in >0.3% of 3500 patients treated with telmisartan monotherapy in controlled or open trials are listed below. It cannot be determined whether these events were causally related to telmisartan tablets:
Autonomic Nervous System: impotence, increased sweating, flushing; Body as a Whole: allergy, fever, leg pain, malaise; Cardiovascular: palpitation, dependent edema, angina pectoris, tachycardia, leg edema, abnormal ECG; CNS: insomnia, somnolence, migraine, vertigo, paresthesia, involuntary muscle contractions, hypoesthesia; Gastrointestinal: flatulence, constipation, gastritis, vomiting, dry mouth, hemorrhoids, gastroenteritis, enteritis, gastroesophageal reflux, toothache, non-specific gastrointestinal disorders; Metabolic: gout, hypercholesterolemia, diabetes mellitus; Musculoskeletal: arthritis, arthralgia, leg cramps; Psychiatric: anxiety, depression, nervousness; Resistance Mechanism: infection, fungal infection, abscess, otitis media; Respiratory: asthma, bronchitis, rhinitis, dyspnea, epistaxis; Skin: dermatitis, rash, eczema, pruritus; Urinary: micturition frequency, cystitis; Vascular: cerebrovascular disorder; and Special Senses: abnormal vision, conjunctivitis, tinnitus, earache.
During initial clinical studies, a single case of angioedema was reported (among a total of 3781 patients treated).
Clinical Laboratory Findings
In placebo-controlled clinical trials, clinically relevant changes in standard laboratory test parameters were rarely associated with administration of telmisartan tablets. Hemoglobin: A greater than 2 g/dL decrease in hemoglobin was observed in 0.8% telmisartan patients compared with 0.3% placebo patients. No patients discontinued therapy due to anemia.
Creatinine: A 0.5 mg/dL rise or greater in creatinine was observed in 0.4% telmisartan patients compared with 0.3% placebo patients. One telmisartan-treated patient discontinued therapy due to increases in creatinine and blood urea nitrogen.
Liver Enzymes: Occasional elevations of liver chemistries occurred in patients treated with telmisartan; all marked elevations occurred at a higher frequency with placebo. No telmisartan-treated patients discontinued therapy due to abnormal hepatic function.
Amlodipine
Amlodipine has been evaluated for safety in more than 11,000 patients in U.S. and foreign clinical trials. Most adverse reactions reported during therapy with amlodipine were of mild or moderate severity. In controlled clinical trials directly comparing amlodipine (n=1730) in doses up to 10 mg to placebo (n=1250), discontinuation of amlodipine due to adverse reactions was required in only about 1.5% of amlodipine-treated patients and was not significantly different from that seen in placebo-treated patients (about 1%). The most common side effects were headache and edema. The incidence (%) of side effects which occurred in a dose-related manner are presented in Table 3.
Table 3: Incidence (%) of Dose-Related Adverse Effects with Amlodipine at Doses of 2.5 mg, 5.0 mg, and 10.0 mg or Placebo
Adverse Event Amlodipine 2.5 mg
n=275
% Amlodipine 5.0 mg
n=296
%
Amlodipine 10.0 mg
n=268
%
Placebo
n=520
%
Edema 1.8 3.0 10.8 0.6 Dizziness
1.1 3.4 3.4 1.5 Flushing
0.7 1.4 2.6 0.0 Palpitations
0.7 1.4 4.5 0.6
Other adverse experiences which were not clearly dose related but which were reported with an incidence greater than 1% in placebo-controlled clinical trials are presented in Table 4.
Table 4: Incidence (%) of Adverse Effects Not Clearly Dose Related but Reported at an Incidence of >1% in Placebo-Controlled Clinical Trials
Adverse Event Amlodipine
n=1730
% Placebo n=1250 %
Headache 7.3 7.8 Fatigue 4.5 2.8 Nausea 2.9 1.9 Abdominal pain 1.6 0.3
Somnolence 1.4 0.6
The following events occurred in <1% but >0.1% of patients in controlled clinical trials or under conditions of open trials or marketing experience where a causal relationship is uncertain; they are listed to alert the physician to a possible relationship:
Cardiovascular:arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, hypotension, peripheral ischemia, syncope, tachycardia, postural dizziness, postural hypotension, vasculitis; Central and Peripheral Nervous System:hypoesthesia, neuropathy peripheral, paresthesia, tremor, vertigo; Gastrointestinal:anorexia, constipation, dyspepsia,** dysphagia, diarrhea, flatulence, pancreatitis, vomiting, gingival hyperplasia, change of bowel habit; General: allergic reaction, asthenia,** back pain, hot flushes, malaise, pain, rigors, weight gain, weight decrease; Musculoskeletal System:arthralgia, arthrosis, muscle cramps,** myalgia; Psychiatric:sexual dysfunction (male** and female), insomnia, nervousness, depression, abnormal dreams, anxiety, depersonalization, mood change; Respiratory System:dyspnea,** epistaxis; Skin and Appendages:angioedema, erythema multiforme, pruritus,** rash,** rash erythematous, rash maculopapular; Special Senses:abnormal vision, conjunctivitis, diplopia, eye pain, tinnitus; Urinary System:micturition frequency, micturition disorder, nocturia; Autonomic Nervous System:dry mouth, sweating increased; Metabolic and Nutritional:hyperglycemia, thirst; Hemopoietic:leukopenia, purpura, thrombocytopenia. **These events occurred in less than 1% in placebo-controlled trials, but the incidence of these side effects was between 1% and 2% in all multiple dose studies.
The following events occurred in <0.1% of patients: cardiac failure, pulse irregularity, extrasystoles, skin discoloration, urticaria, skin dryness, alopecia, dermatitis, muscle weakness, twitching, ataxia, hypertonia, migraine, cold and clammy skin, apathy, agitation, amnesia, gastritis, increased appetite, loose stools, coughing, rhinitis, dysuria, polyuria, parosmia, taste perversion, abnormal visual accommodation, and xerophthalmia.
Other reactions occurred sporadically and cannot be distinguished from medications or concurrent disease states such as myocardial infarction and angina. Amlodipine has not been associated with clinically significant changes in routine laboratory tests. No clinically relevant changes were noted in serum potassium, serum glucose, total triglycerides, total cholesterol, HDL cholesterol, uric acid, blood urea nitrogen, or creatinine.
Amlodipine has been used safely in patients with chronic obstructive pulmonary disease, well-compensated congestive heart failure, coronary artery disease, peripheral vascular disease, diabetes mellitus, and abnormal lipid profiles.
Adverse reactions reported for amlodipine for indications other than hypertension may be found in the prescribing information for Norvasc?.
6.2 Postmarketing Experience
The following adverse reactions have been identified during post-approval use of telmisartan or amlodipine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to telmisartan or amlodipine.
Telmisartan
The most frequently spontaneously reported events include: headache, dizziness, asthenia, coughing, nausea, fatigue, weakness, edema, face edema, lower limb edema, angioneurotic edema, urticaria, hypersensitivity, sweating increased, erythema, chest pain, atrial fibrillation, congestive heart failure, myocardial infarction, blood pressure increased, hypertension aggravated, hypotension (including postural hypotension), hyperkalemia, syncope, dyspepsia, diarrhea, pain, urinary tract infection, erectile dysfunction, back pain, abdominal pain, muscle cramps (including leg cramps), myalgia, bradycardia, eosinophilia, thrombocytopenia, uric acid increased, abnormal hepatic function/liver disorder (more commonly seen in Japanese patients), renal impairment including acute renal failure, anemia, and increased CPK, anaphylactic reaction, tendon pain (including tendonitis, tenosynovitis), drug eruption (e.g. toxic skin eruption mostly reported as toxicoderma, rash, and urticaria), hypoglycemia (in diabetic patients), and angioedema (with fatal outcome).
Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers, including telmisartan.
Amlodipine
Gynecomastia has been reported infrequently and a causal relationship is uncertain. Jaundice and hepatic enzyme elevations (mostly consistent with cholestasis or hepatitis), in some cases severe enough to require hospitalization, have been reported in association with use of amlodipine.
Additionally, confusion, exfoliative dermatitis, Stevens-Johnson Syndrome, and photosensitivity reaction have also been reported.
7 DRUG
INTERACTIONS
7.1 Drug Interactions with TWYNSTA Tablets
The pharmacokinetics of amlodipine and telmisartan are not altered when the drugs are co-administered.
No drug interaction studies have been conducted with TWYNSTA tablets and other drugs, although studies have been conducted with the individual amlodipine and telmisartan components of TWYNSTA tablets, as described below:
7.2 Drug Interactions with Telmisartan
Digoxin: When telmisartan was co-administered with digoxin, median increases in digoxin peak plasma concentration (49%) and in trough concentration (20%) were observed. It is, therefore, recommended that digoxin levels be monitored when initiating, adjusting, and discontinuing telmisartan to avoid possible over- or under-digitalization.
Lithium: Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists including telmisartan. Therefore, monitor serum lithium levels during concomitant use.
Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors): In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2inhibitors, with angiotensin II receptor antagonists, including telmisartan, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving telmisartan and NSAID therapy.
The antihypertensive effect of angiotensin II receptor antagonists, including telmisartan may be attenuated by NSAIDs including selective COX-2inhibitors.
Ramipril and Ramiprilat: Co-administration of telmisartan 80 mg once daily and ramipril 10 mg once daily to healthy subjects increases steady-state C max and AUC of ramipril 2.3- and 2.1-fold, respectively, and C max and AUC of ramiprilat 2.4- and 1.5-fold, respectively. In contrast, C max and AUC of telmisartan decrease by 31% and 16%, respectively. When co-administering telmisartan and ramipril, the response may be greater because of the possibly additive pharmacodynamic effects of the combined drugs, and also because of the increased exposure to ramipril and ramiprilat in the presence of telmisartan. Co-administration of telmisartan and ramipril is not recommended.
Other Drugs: Co-administration of telmisartan did not result in a clinically significant interaction with acetaminophen, amlodipine, glyburide, simvastatin, hydrochlorothiazide, warfarin, or ibuprofen. Telmisartan is not metabolized by the cytochrome P450 system and had no effects in vitro on cytochrome P450 enzymes, except for some inhibition of CYP2C19. Telmisartan is not expected to interact with drugs that inhibit cytochrome P450 enzymes; it is also not expected to interact with drugs metabolized by cytochrome P450 enzymes, except for possible inhibition of the metabolism of drugs metabolized by CYP2C19.
7.3 Drug Interactions with Amlodipine
In clinical trials, amlodipine has been safely administered with thiazide diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, long-acting nitrates, sublingual nitroglycerin, digoxin, warfarin, non-steroidal anti-inflammatory drugs, antibiotics, and oral hypoglycemic drugs.
The following have no clinically relevant effects on the pharmacokinetics of amlodipine: cimetidine, grapefruit juice, Maalox?, sildenafil.
Amlodipine has no clinically relevant effects on the pharmacokinetics or pharmacodynamics of the following: atorvastatin, digoxin, warfarin.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Teratogenic Effects,Pregnancy Categories C (first trimester) and D (second and third trimesters). See Warnings and Precautions(5.1).
8.3 Nursing Mothers
Telmisartan
It is not known whether telmisartan is excreted in human milk, but telmisartan was shown to be present in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, decide whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Amlodipine
It is not known whether amlodipine is excreted in human milk. In the absence of this information, it is recommended to discontinue nursing while amlodipine is administered.
8.4 Pediatric Use
Safety and effectiveness of TWYNSTA in pediatric patients have not been established.
8.5 Geriatric Use TWYNSTA Tablets
Of the total number of 3282 hypertensive patients receiving a telmisartan/amlodipine combination in clinical studies, 605 (18%) patients were 65 years of age or older and of these, 88 (3%) patients were 75 years and older. No overall differences in efficacy or safety of TWYNSTA tablets were observed in this patient population.
Telmisartan
Of the total number of patients receiving telmisartan in clinical studies, 551 (18.6%) were 65 to 74 years of age and 130 (4.4%) were 75 years and older. No overall differences in effectiveness and safety were observed in these patients compared to younger patients 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.
Amlodipine
Clinical studies of amlodipine besylate tablets 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. Elderly patients have decreased clearance of amlodipine with a resulting increase of AUC of approximately 40-60%, and a lower initial dose may be required. Since patients age 75 and older have decreased clearance of amlodipine, start amlodipine or add amlodipine 2.5 mg to
telmisartan. The lowest dose of TWYNSTA is 40/5 mg; therefore, initial therapy with TWYNSTA tablets is not recommended in patients 75 years of age and older [see Dosage and Administration (2.5)].
8.6 Hepatic Insufficiency
Monitor carefully and uptitrate slowly in patients with biliary obstructive disorders or hepatic insufficiency [see Dosage and Administration (2) and Warnings and Precautions (5.4)]. Since patients with hepatic impairment have decreased clearance of amlodipine, start amlodipine or add amlodipine 2.5 mg to telmisartan. The lowest dose of TWYNSTA is 40/5 mg; therefore, initial therapy with TWYNSTA tablets is not recommended in hepatically impaired patients [see Dosage and Administration (2.4)].
8.7 Race
The magnitude of blood pressure lowering in black patients approached that observed in non-black patients but the number of black patients was limited (237 of 1461 patients).
10 OVERDOSAGE Telmisartan
Limited data are available with regard to overdosage in humans. The most likely manifestations of overdosage with telmisartan tablets would be hypotension,
dizziness, and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be instituted. Telmisartan is not removed by hemodialysis.
Amlodipine
Single oral doses of amlodipine maleate equivalent to 40 mg/kg and 100 mg/kg amlodipine in mice and rats, respectively, caused deaths. Single oral doses equivalent to 4 or more mg/kg amlodipine in dogs (11 or more times the maximum recommended human dose on a mg/m 2 basis) caused a marked peripheral vasodilation and hypotension.
Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension. In humans, experience with intentional overdosage of amlodipine is limited. Reports of intentional overdosage include a patient who ingested 250 mg and was asymptomatic and was not hospitalized; another (120 mg) who was
hospitalized underwent gastric lavage and remained normotensive; the third (105 mg) was hospitalized and had hypotension (90/50 mmHg) which normalized following plasma expansion. A case of accidental drug overdose has been documented in a 19-month-old male who ingested 30 mg amlodipine (about 2 mg/kg). During the emergency room presentation, vital signs were stable with no evidence of hypotension, but a heart rate of 180 bpm. Ipecac was administered 3.5 hours after ingestion and on subsequent observation (overnight) no sequelae was noted.
If massive overdose should occur, active cardiac and respiratory monitoring should be instituted. Frequent blood pressure measurements are essential. Should
hypotension occur, cardiovascular support including elevation of the extremities and the judicious administration of fluids should be initiated. If hypotension remains unresponsive to these conservative measures, administration of vasopressors (such as phenylephrine) should be considered with attention to circulating volume and
urine output. Intravenous calcium gluconate may help to reverse the effects of calcium entry blockade. As amlodipine is highly protein bound, hemodialysis is not likely to be of benefit.
11 DESCRIPTION
TWYNSTA is a fixed dose combination of telmisartan and amlodipine.
TWYNSTA tablets contain telmisartan, a non-peptide angiotensin II receptor (type AT 1) antagonist. Telmisartan is a white to slightly yellowish solid. It is practically insoluble in water and in the pH range of 3 to 9, sparingly soluble in strong acid (except insoluble in hydrochloric acid), and soluble in strong base. Telmisartan is
chemically described as 4'-[(1,4'-dimethyl-2'-propyl [2,6'-bi-1H-benzimidazol]-1'-yl)methyl]-[1,1'-biphenyl]-2-carboxylic acid. Its empirical formula is C 33H 30N 4O 2 and its structural formula is:
N
N
N N
CH 3CH
3
OH
O
C H 3
TWYNSTA tablets contain the besylate salt of amlodipine, a dihydropyridine calcium-channel blocker (CCB). Amlodipine besylate is a white to pale yellow crystalline powder, slightly soluble in water and sparingly soluble in ethanol. Amlodipine besylate’s chemical name is 3-Ethyl-5-methyl(4RS)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate benzenesulphonate. Its empirical formula is C20H25ClN2O5?C6H6O3S and its structural formula is:
TWYNSTA tablets are formulated in four strengths for oral administration with a combination of amlodipine besylate, equivalent to 5 mg or 10 mg of amlodipine free-base, with 40 mg, or 80 mg of telmisartan provided in the following four combinations: 40/5 mg, 40/10 mg, 80/5 mg, and 80/10 mg.
TWYNSTA tablets also contain the following inactive ingredients: sodium hydroxide, povidone, meglumine, sorbitol, magnesium stearate, microcrystalline cellulose, pregelatinized starch, corn starch, colloidal silicon dioxide, ferric oxide black, ferric oxide yellow and FD&C blue #1.
TWYNSTA tablets are hygroscopic and require protection from moisture.
TWYNSTA tablets require protection from light.
PHARMACOLOGY
12 CLINICAL
12.1 Mechanism of Action
Telmisartan
Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Telmisartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is therefore independent of the pathways for angiotensin II synthesis.
There is also an AT2 receptor found in many tissues, but AT2 is not known to be associated with cardiovascular homeostasis. Telmisartan has much greater affinity (>3,000 fold) for the AT1 receptor than for the AT2 receptor.
Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because telmisartan does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known. Telmisartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.
Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the effect of telmisartan on blood pressure.
Amlodipine
Amlodipine is a dihydropyridine calcium channel blocker that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Experimental data suggest that amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by amlodipine. Within the physiologic pH range, amlodipine is an ionized compound (pKa=8.6), and its kinetic interaction with the calcium channel receptor is characterized by a gradual rate of association and dissociation with the receptor binding site, resulting in a gradual onset of effect.
Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.
12.2 Pharmacodynamics
TWYNSTA Tablets
TWYNSTA tablets have been shown to be effective in lowering blood pressure. TWYNSTA is a combination of two drugs with antihypertensive properties: a dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker), amlodipine besylate, and an angiotensin II receptor blocker, telmisartan.
Both telmisartan and amlodipine, lower blood pressure by reducing peripheral resistance but through complementary mechanisms.
Telmisartan
In normal volunteers, a dose of telmisartan 80 mg inhibited the pressor response to an intravenous infusion of angiotensin II by about 90% at peak plasma concentrations with approximately 40% inhibition persisting for 24 hours.
Plasma concentration of angiotensin II and plasma renin activity (PRA) increased in a dose-dependent manner after single administration of telmisartan to healthy subjects and repeated administration to hypertensive patients. The once-daily administration of up to 80 mg telmisartan to healthy subjects did not influence plasma
aldosterone concentrations. In multiple dose studies with hypertensive patients, there were no clinically significant changes in electrolytes (serum potassium or sodium), or in metabolic function (including serum levels of cholesterol, triglycerides, HDL, LDL, glucose, or uric acid).
In 30 hypertensive patients with normal renal function treated for 8 weeks with telmisartan 80 mg or telmisartan 80 mg in combination with hydrochlorothiazide 12.5 mg, there were no clinically significant changes from baseline in renal blood flow, glomerular filtration rate, filtration fraction, renovascular resistance, or creatinine clearance.
Amlodipine
Following administration of therapeutic doses to patients with hypertension, amlodipine produces vasodilation resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing. Although the acute intravenous administration of amlodipine decreases arterial blood pressure and increases heart rate in hemodynamic studies of patients with chronic stable angina, chronic oral administration of amlodipine in clinical trials did not lead to clinically significant changes in heart rate or blood pressures in normotensive patients with angina.
With chronic once daily administration, antihypertensive effectiveness is maintained for at least 24 hours. Plasma concentrations correlate with effect in both young and elderly patients. The magnitude of reduction in blood pressure with amlodipine is also correlated with the height of pretreatment elevation; thus, individuals with moderate hypertension (diastolic pressure 105–114 mmHg) had about a 50% greater response than patients with mild hypertension (diastolic pressure 90–104 mmHg). Normotensive subjects experienced no clinically significant change in blood pressure (+1/-2 mmHg).
In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without change in filtration fraction or proteinuria.
As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In hemodynamic studies, amlodipine has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and man, even when co-administered with beta-blockers to man. Similar findings, however, have been observed in normal or well-compensated patients with heart failure with agents possessing significant negative inotropic effects.
Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals or man. In patients with chronic stable angina, intravenous administration of 10 mg did not significantly alter A-H and H-V conduction and sinus node recovery time after pacing. Similar results were obtained in patients receiving amlodipine and concomitant beta-blockers. In clinical studies in which amlodipine was administered in combination with beta-blockers to patients with either hypertension or angina, no adverse effects of electrocardiographic parameters were observed. In clinical trials with angina patients alone, amlodipine therapy did not alter electrocardiographic intervals or produce higher degrees of AV blocks.
Amlodipine has indications other than hypertension which can be found in the Norvasc? package insert.
12.3 Pharmacokinetics
TWYNSTA Tablets
The pharmacokinetics of amlodipine and telmisartan when combined are similar to the pharmacokinetics of amlodipine and telmisartan when administered separately. After administering TWYNSTA 80/10 mg tablet with a high-fat meal, the total area under the plasma concentration-time curve (AUC) and C max for telmisartan decreased by about 24% and 60%, respectively. For amlodipine, AUC and C max were not altered [see Dosage and Administration (2.1)].
Telmisartan
Following oral administration, peak concentrations (C max) of telmisartan are reached in 0.5 to 1 hour after dosing. Food slightly reduces the bioavailability of telmisartan, with a reduction in the area under the plasma concentration-time curve (AUC) of about 6% with the 40 mg tablet and about 20% after a 160 mg dose. The absolute bioavailability of telmisartan is dose dependent. At 40 and 160 mg the bioavailability was 42% and 58%, respectively. The pharmacokinetics of orally administered telmisartan are nonlinear over the dose range 20 to 160 mg, with greater than proportional increases of plasma concentrations (C max and AUC) with increasing doses. Telmisartan shows bi-exponential decay kinetics with a terminal elimination half life of approximately 24 hours. Trough plasma concentrations of telmisartan with once daily dosing are about 10 to 25% of peak plasma concentrations. Telmisartan has an accumulation index in plasma of 1.5 to 2.0 upon repeated once daily dosing.
Amlodipine
Peak plasma concentrations of amlodipine are reached 6-12 hours after administration of amlodipine alone. Absolute bioavailability has been estimated to be between 64% and 90%. The bioavailability of amlodipine is not altered by the presence of food.
Elimination of amlodipine from the plasma is biphasic with a terminal elimination half-life of about 30 to 50 hours. Steady state plasma levels of amlodipine are reached after 7 to 8 days of consecutive daily dosing.
Distribution
Telmisartan
Telmisartan is highly bound to plasma proteins (>99.5%), mainly albumin and α1 - acid glycoprotein. Plasma protein binding is constant over the concentration range achieved with recommended doses. The volume of distribution for telmisartan is approximately 500 liters indicating additional tissue binding.
Amlodipine
The apparent volume of distribution of amlodipine is 21 L/kg. Approximately 93% of circulating amlodipine is bound to plasma proteins in hypertensive patients. Metabolism and Elimination
Telmisartan
Following either intravenous or oral administration of 14C-labeled telmisartan, most of the administered dose (>97%) was eliminated unchanged in feces via biliary excretion; only minute amounts were found in the urine (0.91% and 0.49% of total radioactivity, respectively).
Telmisartan is metabolized by conjugation to form a pharmacologically inactive acylglucuronide; the glucuronide of the parent compound is the only metabolite that has been identified in human plasma and urine. After a single dose, the glucuronide represents approximately 11% of the measured radioactivity in plasma. The cytochrome P450 isoenzymes are not involved in the metabolism of telmisartan.
Total plasma clearance of telmisartan is >800 mL/min. Terminal half-life and total clearance appear to be independent of dose.
Amlodipine
Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism with 10% of the parent compound and 60% of the metabolites excreted in the urine.
Special Populations
Renal Insufficiency
Telmisartan: No dosage adjustment is necessary in patients with decreased renal function. Telmisartan is not removed from blood by hemofiltration [see Warnings and Precautions (5.5)].
Amlodipine: The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. Patients with renal failure may therefore receive the usual initial dose.
Hepatic Insufficiency
Telmisartan: In patients with hepatic insufficiency, plasma concentrations of telmisartan are increased, and absolute bioavailability approaches 100% [see Warnings and Precautions (5.4) and Use in Specific Populations (8.5)].
Amlodipine: Patients with hepatic insufficiency have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40% to 60%. Therefore, start with a low initial dose of amlodipine.
Gender
Plasma concentrations of telmisartan are generally 2–3 times higher in females than in males. In clinical trials, however, no significant increases in blood pressure response or in the incidence of orthostatic hypotension were found in women. No dosage adjustment is necessary.
Geriatric Patients
Telmisartan: The pharmacokinetics of telmisartan do not differ between the elderly and those younger than 65 years [see Dosage and Administration (2.1)].
Amlodipine: Elderly patients have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40% to 60%. Therefore, start with a low initial dose of amlodipine [see Dosage and Administration (2.5)].
TOXICOLOGY
13 NONCLINICAL
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Telmisartan
There was no evidence of carcinogenicity when telmisartan was administered in the diet to mice and rats for up to 2 years. The highest doses administered to mice (1000 mg/kg/day) and rats (100 mg/kg/day) are, on a mg/m2 basis, about 59 and 13 times, respectively, the maximum recommended human dose (MRHD) of telmisartan. These same doses have been shown to provide average systemic exposures to telmisartan >100 times and >25 times, respectively, the systemic exposure in humans receiving the MRHD (80 mg/day).
Genotoxicity assays did not reveal any telmisartan-related effects at either the gene or chromosome level. These assays included bacterial mutagenicity tests with Salmonella and E. coli (Ames), a gene mutation test with Chinese hamster V79 cells, a cytogenetic test with human lymphocytes, and a mouse micronucleus test.
No drug-related effects on the reproductive performance of male and female rats were noted at 100 mg/kg/day (the highest dose administered), about 13 times, on a
mg/m2 basis, the MRHD of telmisartan. This dose in the rat resulted in an average systemic exposure (telmisartan AUC as determined on day 6 of pregnancy) at least 50 times the average systemic exposure in humans at the MRHD (80 mg/day).
Amlodipine
Rats and mice treated with amlodipine maleate in the diet for up to two years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 mg amlodipine/kg/day, showed no evidence of a carcinogenic effect of the drug. For the mouse, the highest dose was, on mg/m2 basis, similar to the maximum recommended human dose [MRHD] of 10 mg amlodipine/day. For the rat, the highest dose was, on a mg/m2 basis, about two and a half times the MRHD. (Calculations based on a 60 kg patient.)
Mutagenicity studies conducted with amlodipine maleate revealed no drug-related effects at either the gene or chromosome level.
There was no effect on the fertility of rats treated orally with amlodipine maleate (males for 64 days and females for 14 days prior to mating) at doses of up to 10 mg amlodipine/kg/day (about 10 times the MRHD of 10 mg/day on a mg/m2 basis).
13.3 Developmental Toxicity
Telmisartan
No teratogenic effects were observed when telmisartan was administered to pregnant rats at oral doses of up to 50 mg/kg/day and to pregnant rabbits at oral doses up to 45 mg/kg/day. In rabbits, embryolethality associated with maternal toxicity (reduced body weight gain and food consumption) was observed at 45 mg/kg/day [about 12 times the maximum recommended human dose (MRHD) of 80 mg on a mg/m2 basis]. In rats, maternally toxic (reduction in body weight gain and food consumption) telmisartan doses of 15 mg/kg/day (about 1.9 times the MRHD on a mg/m2 basis), administered during late gestation and lactation, were observed to produce adverse effects in neonates, including reduced viability, low birth weight, delayed maturation, and decreased weight gain. Telmisartan has been shown to be present in rat fetuses during late gestation and in rat milk. The no observed effect doses for developmental toxicity in rats and rabbits, 5 and 15 mg/kg/day, respectively, are about 0.64 and 3.7 times, on a mg/m2 basis, the maximum recommended human dose of telmisartan (80 mg/day).
Amlodipine
No evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats and rabbits were treated orally with amlodipine maleate at doses of up to 10 mg amlodipine/kg/day (respectively, about 10 and 20 times the maximum recommended human dose [MRHD] of 10 mg amlodipine on a mg/m2 basis) during their respective periods of major organogenesis. (Calculations based on a patient weight of 60 kg.) However, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold) for rats receiving amlodipine maleate at a dose equivalent to 10 mg amlodipine/kg/day for 14 days before mating and throughout mating and gestation. Amlodipine maleate has been shown to prolong both the gestation period and the duration of labor in rats at this dose.
STUDIES
14 CLINICAL
14.1 TWYNSTA Tablets
The efficacy of TWYNSTA tablets for treatment of hypertension was studied in 1 placebo-controlled and 2 active-controlled trials.
An 8-week multicenter, randomized, double-blind, placebo-controlled, parallel group factorial study in patients with mild to severe hypertension was conducted to determine if treatment with TWYNSTA was more effective in reducing blood pressure compared to the respective monotherapies. The study randomized 1461 patients with baseline systolic blood pressure between 117 and 179 mmHg (mean 153 mmHg) and a baseline diastolic blood pressure between 90 and 119 (mean 102 mmHg) to one of the 16 treatment arms. Patients assigned to receive amlodipine 10 mg started on amlodipine 5 mg or combinations thereof for the first two weeks. The four key treatment combinations (including combinations of telmisartan 40 or 80 mg and amlodipine 5 or 10 mg) had statistically significant reduction in in-clinic seated trough cuff systolic and diastolic blood pressure compared to the respective individual monotherapies (Table 5).
Table 5: Placebo-Subtracted Mean Change from Baseline in Seated Systolic/Diastolic Blood Pressure (mmHg):
Combination Therapy vs Monotherapy Components
Amlodipine, mg Telmisartan, mg
0 40 80
0 — -12.1/-7.2
-11.8/-7.8
-19.6/-12.0
5 -12.9/-7.2
-19.3/-10.3
10 -18.2/-10.9 -22.2/-14.0 -23.9/-13.9
The majority of the antihypertensive effect of the telmisartan/amlodipine combination was attained within 2 weeks after initiation of therapy. In patients receiving a telmisartan/amlodipine combination significantly larger reductions in seated diastolic and systolic blood pressure compared to patients treated with the respective monotherapies were observed at every assessment (Week 2, 4, 6, and 8).
The antihypertensive effect of TWYNSTA tablets was similar in patients ≥65 years than below 65 years of age, in male and female patients, and in patients with and without diabetes.
The magnitude of blood pressure lowering in black patients approached that observed in non-black patients but the number of black patients was limited (237 of 1461 patients).
Automated ambulatory blood pressure monitoring (ABPM) performed in a subset of 562 patients confirmed the results seen with in-clinic systolic and diastolic blood pressure reductions over the entire 24-hours dosing period.
In a double-blind, active-controlled study, a total of 1097 patients with mild to severe hypertension (mean baseline systolic/diastolic BP 149.5/96.6 mmHg) who were not adequately controlled on amlodipine 5 mg received TWYNSTA (40/5 mg or 80/5 mg) or amlodipine alone (5 mg or 10 mg). After 8 weeks administration, each of the combination treatments was statistically significantly superior to both amlodipine monotherapy doses in reducing diastolic and systolic blood pressures. Edema related events (peripheral edema, generalized edema, and edema) in patients who received TWYNSTA (40/5 mg or 80/5 mg) were significantly lower as compared to patients who received amlodipine 10 mg (4.3% vs 27.2%, respectively).
Table 6: Effect on Seated Systolic/Diastolic Blood Pressure: Combination Therapy vs Monotherapy
Treatment Group Mean Change1 Difference from amlodipine 5 mg Difference from amlodipine 10 mg
Twynsta 40/5 mg; n=270 -13.6 / -9.4 -7.4* / -3.6* -2.4* / -1.4*
Twynsta 80/5 mg; n=271 -15.0 / -10.6 -8.8* / -4.9* -3.9* / -2.7*
Amlodipine 5 mg; n=255 -6.2 / -5.7 ---- ----
Amlodipine 10 mg; n=261 -11.1 / -8.0 ---- ----
1Mean change from baseline at Week 8 in seated systolic/diastolic blood pressure
In a second double-blind, active-controlled study, a total of 947 patients with mild to severe hypertension (mean baseline systolic/diastolic BP 147.5/95.6 mmHg) who were not adequately controlled on amlodipine 10 mg received TWYNSTA (40/10 mg or 80/10 mg) or amlodipine alone (10 mg). After 8 weeks, each of the combination treatments was statistically significantly superior to amlodipine monotherapy in reducing diastolic and systolic blood pressures.
Table 7: Effect on Seated Systolic/Diastolic Blood Pressure: Combination Therapy vs Monotherapy
Treatment Group Mean Change1 Difference from amlodipine 10 mg
Twynsta 40/10 mg; n=306 -11.1 / -9.2 -3.7* / -2.8*
Twynsta 80/10 mg; n=310 -11.3 / -9.3 -3.9* / -2.8*
Amlodipine 10 mg; n=305 -7.4 / -6.5 ----
1Mean change from baseline at Week 8 in seated systolic/diastolic blood pressure
14.2 Telmisartan
The antihypertensive effects of telmisartan have been demonstrated in six principal placebo-controlled clinical trials, studying a range of 20-160 mg; one of these examined the antihypertensive effects of telmisartan and hydrochlorothiazide in combination. The studies involved a total of 1773 patients with mild to moderate hypertension (diastolic blood pressure of 95 to 114 mmHg), 1031 of whom were treated with telmisartan. Following once daily administration of telmisartan, the magnitude of blood pressure reduction from baseline after placebo subtraction was approximately (SBP/DBP) 6-8/6 mmHg for 20 mg, 9-13/6-8 mmHg for 40 mg, and 12-13/7-8 mmHg for 80 mg. Larger doses (up to 160 mg) did not appear to cause a further decrease in blood pressure.
Upon initiation of antihypertensive treatment with telmisartan, blood pressure was reduced after the first dose, with a maximal reduction by about 4 weeks. With cessation of treatment with telmisartan tablets, blood pressure gradually returned to baseline values over a period of several days to one week. During long term studies (without placebo control) the effect of telmisartan appeared to be maintained for up to at least one year. The antihypertensive effect of telmisartan is not influenced by patient age, gender, weight, or body mass index. Blood pressure response in black patients (usually a low-renin population) is noticeably less than that in Caucasian patients. This has been true for most, but not all, angiotensin II antagonists and ACE inhibitors.
In a controlled study, the addition of telmisartan to hydrochlorothiazide produced an additional dose-related reduction in blood pressure that was similar in magnitude to the reduction achieved with telmisartan monotherapy. Hydrochlorothiazide also had an added blood pressure effect when added to telmisartan.
The onset of antihypertensive activity occurs within 3 hours after administration of a single oral dose. At doses of 20, 40, and 80 mg, the antihypertensive effect of once daily administration of telmisartan is maintained for the full 24-hour dose interval. With automated ambulatory blood pressure monitoring and conventional blood pressure measurements, the 24-hour trough-to-peak ratio for 40 to 80 mg doses of telmisartan was 70 to 100% for both systolic and diastolic blood pressure. The incidence of symptomatic orthostasis after the first dose in all controlled trials was low (0.04%).
There were no changes in the heart rate of patients treated with telmisartan in controlled trials.
14.3 Amlodipine
The antihypertensive efficacy of amlodipine has been demonstrated in a total of 15 double-blind, placebo-controlled, randomized studies involving 800 patients on amlodipine and 538 on placebo. Once daily administration produced statistically significant placebo-corrected reductions in supine and standing blood pressures at 24 hours post-dose, averaging about 12/6 mmHg in the standing position and 13/7 mmHg in the supine position in patients with mild to moderate hypertension. Maintenance of the blood pressure effect over the 24-hour dosing interval was observed, with little difference in peak and trough effect.
16 HOW SUPPLIED/STORAGE AND HANDLING
TWYNSTA tablets are available as non-scored, white–off-white/blue, multilayer tablets of oval, biconvex shape containing telmisartan and amlodipine in the strengths described below. TWYNSTA tablets are debossed with a BOEHRINGER INGELHEIM symbol and an individual product tablet code on one side. TWYNSTA tablets are supplied for oral administration in the following strengths and package configurations:
Tablet strength (telmisartan/ amlodipine equivalent) mg Package
Configuration
NDC# Product
Code
40/5 mg Blister of 30 0597-0124-37 Al
40/10 mg Blister of 30 0597-0125-37 A2
80/5 mg Blister of 30 0597-0126-37 A3
80/10 mg Blister of 30 0597-0127-37 A4
Storage
Store at 25°C (77°F); excursions permitted to 15°–30°C (59°–86°F) [see USP Controlled Room Temperature]. Do not remove from blisters until immediately before administration. Protect from moisture and light.
17 PATIENT COUNSELING INFORMATION
See FDA-Approved Patient Labeling.
17.1 Pregnancy
Inform female patients of childbearing age about the consequences of exposure to drugs that act on the renin-angiotensin system. Advise these patients to report pregnancies to their physicians as soon as possible [see Warnings and Precautions (5.1)].
17. 2 Potential Interference with Mental Alertness, Motor Performance, or Visual Acuity
Since side effects such as syncope, somnolence, dizziness, or vertigo may occur with the use of antihypertensive agents such as TWYNSTA, caution patients about engaging in activities such as driving a vehicle or operating appliances or machinery.
FDA-Approved Patient Labeling
Patient labeling is provided as a tear-off leaflet at the end of this prescribing information.
Norvasc is a registered trademark of Pfizer Inc.
Maalox is a registered trademark of Novartis.
Distributed by:
Boehringer Ingelheim Pharmaceuticals Inc.
Ridgefield, CT 06877 USA
Licensed from: Boehringer Ingelheim International GmbH, Ingelheim, Germany
Copyright 2011 Boehringer Ingelheim International GmbH
ALL RIGHTS RESERVED
OT25024MF202011
71553-08
Patient Information
TWYNSTA? (TWIN-stah)
(telmisartan/amlodipine)
Tablets
Read this Patient Information before you start taking TWYNSTA tablets and each time you get a refill. There may be new information. This information does not take the place of talking to your doctor about your medical condition or your treatment.
What is the most important information I should know about TWYNSTA tablets?
TWYNSTA is not for pregnant women. Taking TWYNSTA tablets during your pregnancy can cause injury and even death to your unborn baby. If you become pregnant, stop taking TWYNSTA tablets and call your doctor right away. If you plan to become pregnant, talk to your doctor about other ways to lower your blood pressure.
What is TWYNSTA?
TWYNSTA is a prescription medicine that contains telmisartan and amlodipine.
TWYNSTA tablets may be used to treat high blood pressure (hypertension):
?when one of these medicines (or a similar one) is not enough to lower your high blood pressure
?as the first medicine to lower your high blood pressure if your doctor decides you are likely to need more than one medicine
It is not known if TWYNSTA is safe and effective in children.
Who should not take TWYNSTA?
You should not take TWYNSTA tablets if you are allergic (hypersensitive) to the active ingredients (telmisartan or amlodipine) or any of the other ingredients listed at the end of this leaflet.
What should I tell my doctor before taking TWYNSTA tablets?
Before you take TWYNSTA tablets, tell your doctor if you:
?have liver problems
?have kidney problems
?have heart problems
?have any other medical conditions
?are pregnant or are planning to become pregnant. See “What is the most important information I should know about TWYNSTA tablets?”
?are breast-feeding or plan to breast-feed. It is not known if TWYNSTA passes into your breast milk. You and your doctor should decide if you will take TWYNSTA tablets or breast-feed. You should not do both. Talk with your doctor about the best way to feed your baby if you take
TWYNSTA tablets.
Tell your doctor about all the medicines you take, including prescription and nonprescription medicines, vitamins and herbal supplements.
TWYNSTA may affect the way other medicines work, and other medicines may affect how TWYNSTA works. Especially tell your doctor if you take:
? digoxin (Lanoxin?, Lanoxicaps?)
? lithium (Eskalith?, Lithobid?)
?medicines used to treat pain and arthritis, called non-steroidal anti-inflammatory drugs (NSAIDs), including COX-2 inhibitors
? ramipril (Altace?) or other medicines that may be used to treat high blood pressure or a heart problem
?water pills (diuretics)
Know the medicines you take. Keep a list of them and show it to your doctor or pharmacist when you get a new medicine.
How should I take TWYNSTA tablets?
?Take TWYNSTA tablets exactly as your doctor tells you to take it.
?Your doctor will tell you how much TWYNSTA to take and when to take it. Your doctor may change your dose if needed.
?Take TWYNSTA one time each day at the same time.
?Take TWYNSTA tablets with or without food.
?If you miss a dose, take it as soon as you remember. If it is close to your next dose, do not take the missed dose. Take the next dose at your regular time.
?If you take too much TWYNSTA, call your doctor or go to the nearest hospital emergency room right away.
?Read the “How to Open the Blister” at the end of this leaflet before you use TWYNSTA. Talk with your doctor if you do not understand the instructions.
What important safety information should I know about TWYNSTA tablets?
?You may experience sleepiness, dizziness, lightheadedness, or fainting when taking medicines such as TWYNSTA tablets. Use caution when engaging in activities such as driving a car or operating appliances or machinery.
What are possible side effects of TWYNSTA tablets?
TWYNSTA tablets may cause serious side effects, including:
?Injury or death to your unborn baby. See “What is the most important information I should know about TWYNSTA tablets?”
?Low blood pressure (hypotension) is most likely to happen if you also:
?take water pills (diuretics)
?are on a low-salt diet
?get dialysis treatments
?have heart problems
?get sick with vomiting or diarrhea
If you feel faint or dizzy, lie down and call your doctor right away.
?Kidney problems. Kidney problems may get worse if you already have kidney disease. You may have changes in your kidney test results, and you may need a lower dose of TWYNSTA tablets. Call your doctor if you get:
?swelling in your feet, ankles, or hands
?unexplained weight gain
Call your doctor right away if you get any of the symptoms listed above.
?Heart problems or heart attack. Heart problems may get worse in people that already have heart disease. This may happen when you start TWYNSTA tablets or when there is an
increase in your dose of TWYNSTA. Get emergency help if you get worse chest pain or chest pain that does not go away.
?High potassium in the blood (hyperkalemia). Your doctor may check your potassium levels as needed.
Rare, serious allergic reactions may happen. Tell your doctor right away if you get any of these symptoms:
?swelling of face, tongue, throat
? difficulty breathing
?blistering of the skin or rash
The most common side effects of TWYNSTA tablets include:
?swelling in your hands, ankles, or feet
?feeling like your heart is pounding or racing
?flushing or sudden redness of the face and neck
? dizziness
? back pain
?feeling tired or sleepy
?abdominal pain, nausea, or diarrhea
?low blood pressure or a sudden drop in blood pressure with fainting
These are not all the possible side effects of TWYNSTA tablets. Tell your doctor if you have any side effect that bothers you or that does not go away.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store TWYNSTA tablets?
?Store TWYNSTA tablets between 59° to 86°F (15° to 30°C).
?Do not remove TWYNSTA tablets from blisters until right before you take them.
?Keep TWYNSTA tablets out of the light and away from moisture.
Keep TWYNSTA tablets and all medicines out of the reach of children.
General information about TWYNSTA tablets
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use TWYNSTA tablets for a condition for which it was not prescribed. Do not give
TWYNSTA tablets to other people, even if they have the same symptoms that you have. It may harm them.
This Patient Information leaflet summarizes the most important information about TWYNSTA tablets. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about TWYNSTA tablets that is written for health professionals. For more information, call Boehringer Ingelheim Pharmaceuticals, Inc. at 1-800-542-6257, or (TTY) 1-800-459-9906.
What are the ingredients in TWYNSTA tablets?
Active ingredients: telmisartan and amlodipine besylate
Inactive ingredients: sodium hydroxide, povidone, meglumine, sorbitol, magnesium stearate, microcrystalline cellulose, pregelatinized starch, corn starch, colloidal silicon dioxide, ferric oxide black, ferric oxide yellow and FD&C blue #1.
What is high blood pressure (hypertension)?
Blood pressure is the force in your blood vessels when your heart beats and when your heart rests. You have high blood pressure when the force is too much. TWYNSTA tablets can help your blood vessels relax so your blood pressure is lower. High blood pressure makes the heart work harder to pump blood throughout the body and causes damage to the blood vessels. If high blood pressure is not treated, it can lead to stroke, heart attack, heart failure, kidney failure, and vision problems.
How to open the blister:
1. Tear (You may also use scissors to tear the blister apart)
2. Peel (Peel off the paper layer from the aluminum foil)
3. Push (Push the tablet through the foil)
Distributed by:
Boehringer Ingelheim Pharmaceuticals, Inc.
Ridgefield, CT 06877 USA
Licensed from: Boehringer Ingelheim International GmbH, Ingelheim, Germany
Copyright 2011 Boehringer Ingelheim International GmbH
ALL RIGHTS RESERVED
Revised: June 2011 OT25024MF202011 71553-08
洛格乐(替米沙坦片)
洛格乐(替米沙坦片) 【药品名称】 商品名称：洛格乐 通用名称：替米沙坦片 英文名称：Telmisartan T ablets 【成份】 本品主要成分为替米沙坦。 【适应症】 治疗原发性高血压。 【用法用量】 1.成人：应个体化给药，常用初始剂量为1片，本品可与噻嗪类利尿药如氢氯噻嗪合用，此类利尿药与本品有协同降压作用。因替米沙坦在用药4至8周后才能发挥最大药效，因此若欲加大药物剂量时，应对此予以考虑。 2.肾功能不全的病人：轻或中度肾功能损害的病人，服用本品不需调整剂量。替米沙坦不能通过血液透析消除。 3.肝功能不全的病人：轻或中度肝功能不全的病人，本品每日用量不应超过1片。 4.老年人：服用本品不需调整剂量。 5.儿童和青少年：对于儿童和18岁以下的青少年，本品的安全性及有效性数据尚未建立。【不良反应】 不良反应按发生频率分为：非常常见(>1/10);常见(>1/100，1/1000，>1/100);罕见(>1/10000，>1/1000);非常罕见(>1/10000)。 1.全身反应。常见：后背痛(如坐骨神经痛)、胸痛、流感样症状、感染症状(如泌尿道感染包
括膀胱炎)。少见：视觉异常、多汗。 2.中枢和外周神经系统：常见：眩晕。 3.胃肠道系统：常见：腹痛、腹泻、消化不良、胃肠功能紊乱。少见：视觉异常、多汗。 4.肌肉骨骼系统：常见：关节痛、腿痉挛或腿痛、肌痛。 5.神经系统：少见：焦虑。 6.呼吸系统：常见：上呼吸道感染包括咽炎和鼻炎。 7.皮肤和附件系统：常见：皮肤异常如湿疹。 8.另外，自替米沙坦上市后，个别病例报告发生红斑、瘙痒、晕厥、失眠、抑郁、胃部不适、呕吐、低血压、心动过缓、心动过速、呼吸困难、嗜酸粒细胞增多症、血小板减少症、虚弱、工作效率下降。与其它血管紧张素Ⅱ拮抗剂相似，极少数病例报道出现血管性水肿、荨麻症和其它相关不良反应。 【禁忌】 1.对本品活性成分及任一种赋形剂成分过敏者。 2.妊娠中末期及哺乳者。 3.胆道阻塞性疾病患者。 4.严重肝功能不全患者。 5.严重肾功能不良患者(肌酐清除率 【注意事项】 1.本品使用过量时若发生症状性低血压应进行支持性治疗，本品不能通过血液透析清除; 2.本品可能会增加抗高血压药物的降压作用; 3.与某些药物合用时应监测血清锂水平。
苯磺酸左旋氨氯地平联合替米沙坦治疗高血压患者的临床效果
苯磺酸左旋氨氯地平联合替米沙坦治疗高血压患者的临床效果 发表时间：2018-06-15T10:20:39.767Z 来源：《世界复合医学》2018年第04期作者：周瑞 [导读] 苯磺酸左旋氨氯地平片联合替米沙坦胶囊治疗高血压患者的疗效更显著，安全性更高。 哈尔滨市阿城金澜医院 150300 【摘要】：目的观察分析苯磺酸左旋氨氯地平片联合替米沙坦胶囊治疗高血压患者的临床疗效。方法选择我院2015年9月-2017年8月收治的原发性高血压患者116例作为本次的研究对象，随机分为对照组和联合组，每组58例。对照组患者采用苯磺酸左旋氨氯地平片进行治疗，联合患者在对照组治疗措施的基础上联合应用替米沙坦胶囊进行治疗。比较两组患者的临床疗效以及治疗前后患者的血压水平变化。结果联合组患者的而临床治疗总有效率为89.66%，明显高于对照组的77.59%，差异有统计学意义（P<0.05）。治疗后，两组患者的SBP以及DBP水平均明显低于治疗前，差异有统计学意义（P<0.05）。与对照组患者治疗后比较，联合组患者治疗后SBP以及DBP水平降低更加显著，差异有统计学意义（P<0.05）。结论苯磺酸左旋氨氯地平片联合替米沙坦胶囊治疗高血压患者的疗效更显著，安全性更高。【关键词】：苯磺酸左旋氨氯地平；替米沙坦；高血压；临床疗效 高血压是指以血压异常升高为主要表现的一种临床疾病，其发病机制尚不完全清晰，目前临床上认为主要与内分泌遗传、中枢神经系统功能紊乱、血脂水平改变等因素相关。高血压临床上可分为原发性高血压和继发性高血压，患者若血压长期得不到有效控制，会严重损害心、脑、肾等器官，极大的威胁患者的健康和生命[1]。2015年9月-2017年8月，我科联合应用苯磺酸左旋氨氯地平片与替米沙坦胶囊治疗了高血压患者，取得的临床疗效显著，现报告如下。 1 资料与方法 1.1一般资料选择我院2015年9月-2017年8月收治的原发性高血压患者116例作为本次的研究对象，随机分为对照组和联合组，每组58例。其中，联合组男性患者33例，女性患者25例，年龄29-75岁，平均年龄（54.1±8.4）岁，病程7个月-18年，平均病程（9.3± 2.3）年。对照组男性患者31例，女性患者27例，年龄28-78岁，平均年龄（54.3±8.9）岁，病程5个月-20年，平均病程（9.5±2.2）年。两组患者的基本资料之间比较，差异均无统计学意义（P＞0.05），具有可比性。 1.2治疗方法对照组患者应用苯磺酸左旋氨氯地平片进行治疗， 2.5-5mg/d。联合组患者在对照组患者治疗措施的基础上联合应用替米沙坦胶囊进行治疗，40-80mg/d。两组患者连续治疗8周。 1.3观察指标①临床疗效。显效为患者治疗后舒张压（DBP）下降＞10 mm Hg，下降到正常范围，或者下降＞20 mm Hg，但未降到正常范围。有效为患者的DBP下降＜10mm Hg，但已下降到正常范围，或者下降10～20 mm Hg，或者收缩压（SBP）下降＞30 mm Hg。无效为患者的血压水平未达到上述标准。总有效率=(显效例数+有效例数)/总例数×100%。②比较两组患者治疗前后SBP以及DBP水平。 1.4统计学处理采用SPSS17.0软件对数据进行统计分析，计数资料率的比较采用x2检验，计量资料组间比较采用t检验，当P<0.05时，为差异有统计学意义。 2 结果 2.1两组患者的临床疗效比较如表1所示，联合组患者的而临床治疗总有效率为89.66%，明显高于对照组的77.59%，差异有统计学意义（P<0.05）。 表1 两组患者的临床疗效比较[例（%）] 2.2两组患者治疗前后SBP以及DBP水平比较如表2所示，治疗后，两组患者的SBP以及DBP水平均明显低于治疗前，差异有统计学意义（P<0.05）。与对照组患者治疗后比较，联合组患者治疗后SBP以及DBP水平降低更加显著，差异有统计学意义（P<0.05）。 表2 两组患者治疗前后SBP以及DBP水平比较（x±s，mmHg） 3 讨论 高血压是严重危害人类身体健康的慢性疾病，近年来发病率呈上升趋势，高血压可以导致心脑肾靶器官损害，高血压是引起心血管病的主要危险因素。苯磺酸左旋氨氯地平是二氢吡啶类钙拮抗剂，可选择性抑制钙离子跨膜进入平滑肌细胞和心肌细胞，对平滑肌的作用大于心肌。长期使用不会显著改变心率或血浆儿茶酚胺，降压效果平稳，峰谷值差别不大该药物的拮抗活性约为常规消旋体的2倍，故采用消旋体药物一半的剂量便可达到有效的临床效果，良好的保证了用药的安全性。此外，与普通的钙离子拮抗剂相比，苯磺酸左旋氨氯地平具有药效作用快、降压迅速、激活机体交感系统等优势特点[2]。替米沙坦片可与血管紧张素受体AT1 结合，消除血管紧张素Ⅱ引起的血管收缩，水钠潴留，使外周阻力降低，动脉血压下降，使左心室前后负荷下降，减轻左心室肥厚，改善心脏功能，同时可保护肾脏功能，减少蛋白尿，在治疗开始后 4 周可获得最大降压效果，并可在长期治疗中维持[3]。本次研究结果显示，联合组患者的而临床治疗总有效率为89.66%，明显高于对照组的77.59%；与对照组患者治疗后比较，联合组患者治疗后SBP以及DBP水平降低更加显著，差异有统计学意义（P<0.05）。综上所述，苯磺酸左旋氨氯地平片联合替米沙坦胶囊治疗高血压患者的疗效更显著，安全性更高。 参考文献 [1]王清辉，徐丽英.苯磺酸左旋氨氯地平与替米沙坦片治疗原发性高血压的疗效及成本效果分析[J].临床医药实践,2016,25(1):73-75.
六种沙坦类降压药物之间的超详细比较
六种沙坦类降压药物之间的超详细比较 血管紧张素受体拮抗剂（ARB）包括缬沙坦、厄贝沙坦、氯沙坦等，是临床常用的一类降压药物。虽同属ARB，但不同品种之间也有所区别。 一、医保情况降压药需要长期服用，建议选择《国家基本医疗保险、工伤保险和生育保险药品目录》中的品种。 二、适应症药品说明书和临床诊疗指南均是医生开具处方的依据。1.氯沙坦在ARB（沙坦类）降压药物中，迄今为止仅发现氯沙坦在降压药的同时，兼有降尿酸作用，并可降低痛风发作风险。2.缬沙坦、坎地沙坦、氯沙坦ACEI/ARB能降低慢性心力衰竭（HFrEF）患者的住院风险和死亡率，并能改善症状和运动能力。无禁忌症和可耐受者首选ACEI（普利类），不能耐受ACEI者推荐选用ARB（沙坦类）。在ARB的使用上，为避免类推效应扩大化，《中国心力衰竭诊断和治疗指南2018》仅推荐有明确试验证据的ARB类药物，如坎地沙坦、缬沙坦、氯沙坦。 三、用法用量和服药时间 1.缬沙坦进餐时服用可使生物利用度减少48%。如果患者可耐受，建议早晨空腹服用。2.坎地沙坦酯坎地沙坦酯可能引起低血糖症（易发生在糖尿病患者中），建议早餐后服用。
温馨提示：1.高血压合并糖尿病：首选ACEI/ARB。如需联合用药，应以ACEI/ARB为基础，加用其他降压药。2.慢性心力衰竭（HFrEF）：首选ACEI/ARB。从小剂量开始，逐步增加至目标剂量或可耐受剂量（见下表）。注意：起始剂量、目标剂量、用药频次，与用于降压时的区别。四、相互作用不同点：1.替米沙坦替米沙坦可升高地高辛的谷浓度（约20%），当与地高辛合用时须监测地高辛血药浓度。 2.氯沙坦氯沙坦及代谢产物（E-3174）均有降压作用，利福平和氟康唑可降低活性代谢产物水平，但临床意义不明确。 四、共同点： 1.与非甾体抗炎药合用：非甾体抗炎药（布洛芬、依托考昔等），一是降低ARB的降压作用，二是增加肾损害风险。 2.与噻嗪类利尿剂合用：利尿药可以刺激肾素分泌，正在使用利尿剂的患者初次使用ARB时，应从小剂量开始，否则可能引起严重的低血压。
PRoFESS研究结果及分析
在第十七届欧洲卒中会议上公布的PRoFESS?研究结果 研究概述 PRoFESS研究是为预防脑卒中复发而进行的有史以来最大规模的临床试验。欧洲东部时间5月14日在法国尼斯举行的第十七届欧洲卒中会议（EStC）上正式公布了这项研究的结果。PRoFESS?是在35个国家的695个临床试验中心进行的一项双盲、安慰剂对照研究，有20,332例患者被随机分组接受了Aggrenox ?（缓释潘生丁（200mg）+阿司匹林（25 mg），每天两次）或氯吡格雷（75 mg）每天一次，并同时随机选择性给予80mg美卡素?（替米沙坦）或安慰剂。 研究结果 关于Aggrenox?（中文商品名：艾诺思?）vs 氯吡格雷 尽管两种抗血小板治疗方案的主要及次要研究结果事件发生率均几乎相同，但本研究未能达到非劣效性标准。换言之，艾诺思没有被证实与氯吡格雷疗效相当，但也未被证实疗效劣于氯吡格雷。 关于替米沙坦（美卡素?）vs 安慰剂 在经过平均2.5年的随访后，替米沙坦组与安慰剂组发生卒中的患者比例无显著差别（两组分别为8.7％及9.2％；风险比[HR] 0.95，95％可信区间[CI] 0.86-1.04，p= 0.23）。 替米沙坦与安慰剂相比，两个次要研究结果均未出现显著减少：1）主要血管事件（心血管死亡、心肌梗死、卒中以及新出现的心力衰竭或心力衰竭恶化）（两组分别为13.5 ％及14.4 ％，HR 0.94，95％CI 0.87-1.01，p=0.11 ）; 2）新发糖尿病发生例数（替米沙坦组为125 例，而安慰剂组为151；HR 0.82，95％CI 0.65 - 1.04，p=0.10） 但是，探索性分析提示：在研究的最初6个月内，两组患者脑卒中或主要血管事件的复发率不存在差异（脑卒中：替米沙坦组3.4％vs. 安慰剂组3.2％；HR 1.07，95％CI 0.92-1.25，p=0.38；主要血管事件：替米沙坦组4.7％vs. 安慰剂组4.3％；HR 1.10，95％CI 0.97-1.26，p= 0.14）。然而6个月后，替米沙坦组的两项复发率均显著低于安慰剂组（脑卒中：替米沙坦组5.3％vs. 安慰剂组6.0％；HR 0.88，95％CI 0.78-0.99，p=0.029 ；主要血管事件：替米沙坦组8.8％vs. 安慰剂组10.1 ％；HR 0.87，CI 0.80-0.95，P= 0.0029）。 专家意见 Salim Yusuf教授（本试验的三个主要研究者之一）：“试验表明：在卒中后早期仅以平均3.5 mmHg的中度血压下降幅度治疗约2.5年，这样的治疗强度和持续时间可能并不足以用来可靠地评价降低血压是否对于卒中后患者具有临床应用价值。” Hans-Christoph Diener教授（本试验的三个主要研究者之一）：“我们需要进行血压降幅更大、疗程更长的临床试验来对这一假设进行检验”。
欧美宁(替米沙坦片)
欧美宁(替米沙坦片) 【药品名称】 商品名称：欧美宁 通用名称：替米沙坦片 英文名称：Telmisartan T ablets 【成份】 替米沙坦 【适应症】 用于原发性高血压的治疗。 【用法用量】 成人: 应个体化给药。常用初始剂量为每次一片(40mg),每日一次。在20～80 mg的剂量范围内，替米沙坦的降压疗效与剂量有关。若用药后未达到理想血压可加大剂量，最大剂量为80 mg，每日1次。本品可与噻嗪类利尿药如氢氯噻嗪合用，此类利尿药与本品有协同降压作用。因替米沙坦在疗程开始后四至八周本品才能发挥最大药效，因此若欲加大药物剂量时，应对此予以考虑。肾功能不全的病人轻或中度肾功能不良的病人，服用本品不需调整剂量。替米沙坦不通过血过滤消除。肝功能不全的病人轻或中度肝功能不全的病人，本品用量每日不应超过40mg。老年人服用本品不需调整剂量。儿童和青少年对于儿童和18岁以下的青少年，本品的安全性及有效性数据尚未建立。 【不良反应】 在安慰剂对照试验中，替米沙坦(41.4%)的不良事件总发生率和安慰剂(43.9%)相似。不良事件的发生和剂量无相关性，与患者性别、年龄和种族亦无关。以下所列的不良反应是从临床试验中接受替米沙坦治疗的5788名高血压患者累计得到的。不良反应按发生频率分
为：非常常见(>1/10);常见(>1/100,1/1000,1/10000, 【禁忌】 对本品活性成分及任一种赋形剂成分过敏者妊娠中末期及哺乳者胆道阻塞性疾病患者严重肝功能不全患者严重肾功能不良患者(肌酐清除率﹤30ml/分钟) 【注意事项】 肝功能不全本品不得用于胆汁淤积、胆道阻塞性疾病或严重肝功能障碍的患者，因为替米沙坦绝大部分通过胆汁排泄，而这些患者对本品的清除率可能降低。本品应慎用于轻中度肝功能不全患者。肾血管性高血压对于双侧肾动脉狭窄或单侧功能肾肾动脉狭窄的病例，使用可影响肾素-血管紧张素-醛固酮系统的药物而导致严重的低血压和肾功能不全的危险性增高。肾功能不全和肾移植患者本品不得用于严重肾功能不全患者(肌酐清除率﹤30 mL/分钟，参见禁忌症)。对于肾功能不全的患者，使用本品期间，应定期检测血钾水平及血肌酐值。尚无新近进行肾移植后短期内的患者使用本品的资料。血容量不足患者对于因使用强利尿剂治疗、限盐饮食、恶心或呕吐引起血容量不足或血钠水平过低的患者，服用本品，特别是初次服用后，可能导致症状性低血压。因而，在使用本品之前，应先纠正血钠及血容量水平。与刺激肾素-血管紧张素-醛固酮系统有关的其它情况对于血管张力以及肾功能主要依赖于肾素-血管紧张素-醛固酮系统活性的病人(如严重充血性心力衰竭或包括肾动脉狭窄的潜在肾脏疾病的患者)，使用可影响该系统的药品，可引起急性低血压、高氮血症、少尿，或罕见急性肾功能衰竭。原发性醛固酮增多症抑制肾素-血管紧张素-醛固酮系统的抗高血压药物通常对原发性醛固酮增多症的患者无效，因此本品不推荐用于该类患者。主动脉瓣或二尖瓣狭窄、阻塞性肥厚性心肌病与使用其它血管扩张剂相同，主动脉瓣或二尖瓣狭窄、阻塞性肥厚性心肌病患者使用本品应特别注意。电解质不平衡：高钾血症使用可影响肾素-血管紧张素-醛固酮系统的药品，可能引起高钾血症，尤其对于肾功能不良和/或心衰
替米沙坦联合氨氯地平治疗老年轻中度高血压患者60例
替米沙坦联合氨氯地平治疗老年轻中度高血压患者60例 李华波 （湖北民族学院附属民大医院心内科，湖北 恩施445000） 〔关键词〕替米沙坦；氨氯地平；高血压〔中图分类号〕R743.3 〔文献标识码〕A 〔文章编号〕1005-9202（2012）21-4784-02；doi ：10.3969/j.issn.1005-9202.2012.21.092 第一作者：李光波（1975-），男，硕士，副主任医师，主要从事心血管疾病 的临床诊治工作。 目前我国高血压患病率高达15% 20%，但知晓率、治疗率、控制率分别仅为30.2%、 24.7%和61%〔1〕 。因而如何对原 发性高血压进行及时、有效地控制已成为临床医师的当务之急。作为最主要的降压手段之一，药物降压常以钙通道阻滞剂为主。因此，本研究选择较为常用的一线药物，探讨替米沙坦联合氨氯地平治疗老年轻中度高血压的可行性。1对象与方法 1.1 对象2011年3月至2012年5月确诊的120例老年中 轻度高血压患者，均符合1999年WHO 制定的高血压标准，即收缩压（SBP ）＞140mmHg 和（或）舒张压（DBP ）＞90mmHg ，且均排除冠心病、糖尿病、心力衰竭及严重的肝肾损害等疾病。其中男71例，女49例，年龄42 83〔平均（60.8?12.6）〕岁。所有患者在知情同意的基础上按照就诊的先后顺序随机分成两组，其中对照组60例单行氨氯地平治疗，观察组60例联合替米沙坦。两组患者的年龄、 性别、病情等一般资料比较无显著性差异（均P ＞0.05），可排除药物因素影响。1.2 治疗及评价方法 全部患者均停用原有降压药物清洗 2w ，对照组患者给予口服氨氯地平片5mg /d ；观察组患者在对照组治疗基础上给予口服替米沙坦片40mg /次， 2次/d ，4w 为一个疗程，连续治疗2个疗程。两组分别治疗4w 后测坐位血压。采用SF-36生命质量量表〔包括总体健康（GH ），生理功能（PF ），生理职能（RP ），社会功能（SF ），情感职能（RE ），精神健 康（MH ）〕评价患者的生活质量变化〔2〕 。 1.3统计学方法 应用SPSS13.0统计软件进行分析，数据资 料以x ?s 表示， 采用t 检验对计量资料进行组间显著性检验，采用χ2 检验对计数资料进行比较。2结 果 2.1 治疗前后两组患者动脉血压、心率比较 治疗后所有患 者的SBP 、DBP 、心率HR 均明显优于治疗前（P ＜0.05）。两组间比较，观察组患者均优于对照组（P ＜0.05）。见表1。2.2 治疗后两组患者日常生活自理能力（ADL ）分级及并发症 发生率对比 治疗后两组间比较，观察组患者的并发症发生 率、 ADL 分级均优于对照组（P ＜0.05）。见表2 。
苯磺酸氨氯地平片英文说明书
HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use amlodipine besylate tablets safely and effectively. See full prescribing information for amlodipine besylate tablets. Amlodipine Besylate Tablets Initial U.S. Approval: 1987 INDICATIONS AND USAGE Amlodipine besylate tablets are a calcium channel blocker and may be used alone or in combination with other antihypertensive and antianginal agents for the treatment of: ?Hypertension ( ) 1.1 ?Coronary Artery Disease ( ) 1.2 ?Chronic Stable Angina ?Vasospastic Angina (Prinzmetal's or Variant Angina)?Angiographically Documented Coronary Artery Disease in patients without heart failure or an ejection fraction < 40% DOSAGE AND ADMINISTRATION ?Adult recommended starting dose: 5 mg once daily with maximum dose 10 mg once daily. ( ) 2.1 ?Small, fragile, or elderly patients, or patients with hepatic insufficiency may be started on 2.5 mg once daily. ( ) 2.1 ?Pediatric starting dose: 2.5 mg to 5 mg once daily. ( ) 2.2 : Doses in excess of 5 mg daily have not been studied in pediatric patients. ( ) Important Limitation2.2 DOSAGE FORMS AND STRENGTHS ? 2.5 mg, 5 mg, and 10 mg Tablets ( ) 3 CONTRAINDICATIONS ?Known sensitivity to amlodipine ( ) 4 WARNINGS AND PRECAUTIONS ?Symptomatic hypotension is possible, particularly in patients with severe aortic stenosis. However, because of the gradual onset of action, acute hypotension is unlikely. ( ) 5.1 ?Worsening angina and acute myocardial infarction can develop after starting or increasing the dose of amlodipine, particularly in patients with severe obstructive coronary artery disease. ( ) 5.2 ?Titrate slowly when administering calcium channel blockers to patients with severe hepatic impairment. ( ) 5.4 ADVERSE REACTIONS Most common adverse reactions are headache and edema which occurred in a dose related manner. Other adverse experiences not dose related but reported with an incidence >1% are headache, fatigue, nausea, abdominal pain, and somnolence. ( ) 6 To report SUSPECTED ADVERSE REACTIONS, contact Qualitest Pharmaceuticals at 1-800-444-4011 or FDA at 1-800-FDA-1088 or https://www.docsj.com/doc/5510905842.html,/medwatch. To report SUSPECTED ADVERSE REACTIONS, contact at or FDA at 1-800-FDA-1088 or https://www.docsj.com/doc/5510905842.html,/medwatch USE IN SPECIFIC POPULATIONS ?Pregnancy: Use only if the potential benefit justifies the potential risk. ( ) 8.1 ?Nursing: Discontinue when administering amlodipine. ( ) 8.3?Pediatric: Effect on patients less than 6 years old is not known. ( ) 8.4?Geriatric: Start dosing at the low end of the dose range, due to the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. ( ) 8.5 Revised: 05/2010 FULL PRESCRIBING INFORMATION: CONTENTS * 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 6 ADVERSE REACTIONS 7 DRUG INTERACTIONS 7.10 Drug/Laboratory Test Interactions 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics and Metabolism 12.4 Pediatric Patients 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES AMLODIPINE 5MG TABLET * Sections or subsections omitted from the full prescribing information are not listed
替米沙坦不同给药时间治疗高血压的疗效研究
替米沙坦不同给药时间治疗高血压的疗效研究 目的研究不同给药时间使用替米沙坦治疗高血压的疗效。方法选取2013年1月～2015年1月我院收治的高血压患者86例作为研究对象，统一对其实施替米沙坦进行治疗，按照各自服药时间的不同分为晨起服药组与晚间服药组，各43例。分析两种服药时间的疗效差异。结果治疗后两组患者血压水平均得到控制，大部分患者血压水平稳定至正常范围内，其中晚间服药组患者血压下降程度更为显著，差异有统计学意义（P＜0.05）；治疗前两组患者均为非杓型高血压，经治疗，晨起服药组患者有13例转为杓型高血压，转变率为30.23%；晚间服药组患者中有29例转为杓型高血压，转变率为67.44%。晚间服药组转变率更高，差异有统计学意义（P＜0.05）。结论晨起或晚间对患者实施替米沙坦治疗高血压均可以起到较好的降压作用，但晚间服药更利于患者血压类型的转变，临床应根据患者实际情况，合理选择用药时间。 标签：不同给药时间；高血压；替米沙坦；疗效 高血压发病率较高，且会引发多种并发症，给人们的生命健康带来严重威胁。由高血压引发的并发症主要是靶器官受损，其损伤程度与血压水平的高低紧密相联，因此有学者认为，高血压治疗的目的是对相关重要靶器官进行保护。目前高血压以药物治疗为主，而掌握最佳用药时间是提高疗效必不可少的环节[1]。本文主要在不同给药时间对高血压患者实施替米沙坦进行治疗，并分析疗效，现报道如下。 1 资料与方法 1.1 一般资料 回顾性分析2013年1月～2015年1月我院收治的高血压患者86例的临床资料，入院后对患者进行统一常规检查，检查结果符合《中国高血压防治指南》（2010年版）中所规定的相关诊断标准[2]。入院前两周患者无相关降压药物使用史，本次研究排除有心衰或心梗症状、呼吸暂停综合征、血糖水平过高等患者。按照各自服药时间的不同分为晨起服药组与晚间服药组，各43例。晨起服药组男27例，女16例，平均年龄（69.57±2.8）岁，平均病程（5.42±1.31）年； 晚间服药组男28例，女15例，平均年龄（68.93±2.9）岁，平均病程（5.39±1.29）年。两组患者一般资料对比，差异无统计学意义（P>0.05）。患者知晓并签订相关知情同意书，报医院伦理委员会批准。 1.2 方法 本次所用药物为替米沙坦（Boehringer Ingelheim Pharma GmbH & Co. KG，批准文号H20090063），晨起服药组患者于8：00口服80 mg；晚间服药组患者于20：00口服80 mg，持续治疗12周。
药品“替米沙坦片” 市场推广报告
药品“替米沙坦片”市场推广报告 报告区域： 报告类型： 委托人： 受托人： 版本号： 2020年XX月XX日发布
公司简介 【公司名称】：常州亚邦制药有限公司 【成立时间】：2002年10月 【地址】：位于江苏省常州市金坛区经济开发区良常东路6号， 【注册资本】：7000万元， 【经营范围】：化学原料药的生产和销售。 公司占地面积8万平方米，建筑面积14000平方米，总投资超1亿，拥有符合药品GMP要求的6条精烘包生产线、5个合成车间、1个加氢车间、1个化验中心和1个研发中心，一套污水处理装置及环保设施，绿 化占地面积≥40%以上，形成500吨/年原料药及医药中间体的专业公司。 公司现拥有国家注册批准文号产品49个，其中通过药品GMP认证 的品种有：呋塞米、丙谷胺、盐酸普萘洛尔、细辛脑、肾上腺色腙、 氯雷他定、苯磺酸氨氯地平、替米沙坦、盐酸小檗碱等32个。 公司实现年销售2亿元以上，近年来先后被评为金坛市“环保先进企业”、“江苏省先进节水型企业”；2007年度通过ISO14000审核认证；2009年度被认定为“江苏省高新技术企业”并已通过复审；“盐 酸小檗碱”被认定为江苏省高新技术产品；2010年通过江苏省“强制 性清洁生产”审核，2013年再次通过ISO14000体系审核认证,2015年获得“安全生产标准化二级企业（危化）”。 公司现有员工285余人，其中大专以上科技人员占40%以上，并拥有药物研发、原料药合成的教授、博士、硕士等高科技人才十几人，拥有自主申请专利十几项。亚邦制药公司发扬“团结、奋进、严谨、
高效”的企业精神，遵循“人才为本，科技为先、品质为上、信义为重”的经营理念，努力创建良好队伍，良好管理，致力于科技关爱健康，向社会奉献质优产品。
替米沙坦不同给药时间治疗高血压的疗效分析研究
替米沙坦不同给药时间治疗高血压的疗效分析研究 摘要目的探究替米沙坦不同给药时间治疗高血压的临床效果。方法120例高血压患者，随机分为实验组与对照组，各60例。两组患者均通过替米沙坦进行治疗，其中，对照组于早晨给药，实验组于夜间给药，对比两组患者临床治疗效果。结果治疗后，实验组杓型血压比例为61.7%，对照组杓型血压比例为26.7%，实验组明显高于对照组，差异具有统计学意义（P＜0.05）；两组患者治疗前后血压控制情况比较差异无统计学意义（P>0.05）。结论针对高血压患者，替米沙坦临床治疗效果显著，且夜间给药更有利于改善患者血压异常波动情况，增加杓型血压比例，值得临床广泛推广应用。 关键词替米沙坦；给药时间；高血压；临床效果 高血压，属于心脑血管疾病范畴，在临床上较为常见，易导致患者生活质量受到影响[1，2]。替米沙坦，是一种降压药物，在高血压疾病治疗中得到广泛应用[2，3]。为探究替米沙坦不同给药时间治疗高血压的临床效果，本院以2014年9月～ 2015年9月期间到本院参与治疗的120例高血压患者为对象，通过夜间和早晨给药，取得了一定成效，现报告如下。 1 资料与方法 1. 1 一般资料选取2014年9月～2015年9月期间到本院参与治疗的高血压患者120例，所有患者均符合高血压诊断标准，采用随机分组方式将其分为实验组与对照组，各60例。对照组男34例、女26例，年龄35～80岁，平均年龄（54.2±8.6）岁， 病程1～15年，平均病程（6.5±2.9）年。实验组男31例、女29例，年龄37～78岁，平均年龄（56.1±8.3）岁，病程2～13年，平均病程（7.3±1.9）年。两组患者性别、年龄、病程等一般资料比较差异无统计学意义（P>0.05），具有可比性。 1. 2 方法对照组：早晨给药，即晨起8：00时给替米沙坦，以80 mg/次为标准，坚持1次/d。实验组：夜间给药，即晚上8：00时给替米沙坦，以80 mg/次为标准，坚持1次/d。两组患者均以1个月为治疗时间[3，4]。 1. 3 观察指标及判定标准①（dSBP-nSBP）/dSBP10%，即标志着杓型血压，（dSBP-nSBP）/dSBP＜10%，则标志着非杓型血压。②详细记录患者24 h 收缩压（SBP）和舒张压（DBP），并对比分析。 1. 4 统计学方法采用SPSS20.0统计学软件对数据进行统计分析。计量资料以均数±标准差（x-±s）表示，采用t检验；计数资料以率（%）表示，采用
苯磺酸氨氯地平片说明书
苯磺酸氨氯地平片说明书 苯磺酸氨氯地平片主要适用于高血压和心绞痛！本文是品才网小编精心编辑的苯磺酸氨氯地平片相关资料，希望能帮助到你！ 产品品名苯磺酸氨氯地平片主要原料苯磺酸氨氯地平主要作用高血压。心绞痛：尤其自发性心绞痛。产品规格5mg*7s 用法用量通常口服起始剂量为5mg，每日一次，最大不超过10mg，每日一次。瘦小者、体质虚弱者、老年患者或肝功生产企业广东彼迪药业有限公司苯磺酸氨氯地平片说明书【药品名称】 通用名称：苯磺酸氨氯地平片 商品名称：苯磺酸氨氯地平片 英文名称：Amlodipine Besylate Tablets 【主要成份】苯磺酸氨氯地平 【成份】 化学名：3-乙基-5-甲基-2-(2-氨基乙氧甲基)-4-(2-氯苯基)-1，4-二氢-6-甲基-3， 5-吡啶二羧酸酯苯磺酸盐分子式：C20H25N2O5Cl?C6H6O3S
分子量： 【性状】本品为白色片。 【适应症/功能主治】 (1)高血压(单独或与其他药物合并使用)。(2)心绞痛：尤其自发性心绞痛(单独或与其他药物合并使用)。 【规格型号】5mg*7s 【用法用量】通常口服起始剂量为5mg，每日一次，最大不超过10mg，每日一次。瘦小者、体质虚弱者、老年患者或肝功 【不良反应】本品在10mg/日的剂量范围内有良好的耐受性，大多数不良反应是轻中度的。本品因不良反应而停药的仅为%，与安慰剂没有明显差别(约1%)。最常见的不良反应是头痛和水肿。发生率1%的剂量相关性不良反应如下：水肿、头晕、潮红和心悸。与剂量关系不明确，但发生率超过%的不良反应如下：头痛、疲倦、恶心、腹痛和嗜睡。以上不良反应中，水肿、潮红、心悸和嗜睡在女性中的发生率超过男性。以下不良事件发生率?1%但%，与药物的因果关系不明确：一般：过敏反应，虚弱，背痛，潮热，不适，疼痛，僵硬，体重增加;心血管：心律失常(包括心动过速、心动过缓或房颤)，胸痛，低血压，外周缺血，昏厥，体位性头晕，
替米沙坦片联合硝苯地平缓释片(Ⅰ)治疗原发性高血压临床观察
替米沙坦片联合硝苯地平缓释片（Ⅰ）治疗原发性高血压临床观察 高血压病是严重危害人类健康最常见的疾病之一，是我国老年人最常见的心脑血管疾病的主要危险因素。按照2012年社区慢性病成人血压普查材料估计，我国成人高血压患病率约成人总数的20.4%。但治疗状况不能令人满意。原发性高血压目前尚无根治方法。大规模临床试验证明，收缩压下降10～20mmHg或舒张压下降5～6mmHg，3～5年内脑卒中、心脑血管病病死率与冠心病事件可分别减少38.0%、20.0%与16.0%，从而奠定了降压治疗的临床地位，特别是老年或有合并症的高危患者能获得更大的益处[1]。我们用替米沙坦片联合硝苯地平缓释片（Ⅰ）治疗老年原发性高血压疗效较好，现报道如下： 1资料与方法 1.1一般资料通过我院对社区居民体检发现的55岁以上血压升高者中，筛选90例符合WHO/ISH关于高血压诊断标准的患者，并排除伴有严重心、脑、肾并发症和继发性高血压患者。90例患者分成A、B、C三组，每组各30例。A 组男性15例，女15例，1级3例（10.0%），2级25例（83.3%），3级2例（6.7%）。B组男性16例，女14例，1级4例（13.4%），2级25例（83.3%），3级1例（3.3%）。C组男性15例，女15例，1级2例（6.7%），2级27例（90.0%），3级1例（3.3%）。伴或不伴分数异常。三组患者在年龄、性别、高血压程度方面基本一致。 1.2方法A组口服替米沙坦片，40mg，1次/d；B组口服硝苯地平缓释片（Ⅰ），10mg～20mg，2次/d；C组口服替米沙坦片，40mg，1次/d、硝苯地平缓释片（Ⅰ），10mg，2次/d。三组疗程均为4w，由专人测定血压，第1w 1次/d，第2w起测2～3次/w。 1.3疗效评定标准①显效：舒张压下降>10mmHg并降至正常，或收缩压下降>20mmHg；②有效：舒张压下降30mmHg；③无效：血压下降未达有效标准。 总有效=显效+有效。 2结果 2.1三组疗效比较，见表1。 由表1可以看出，三组患者治疗4w后，C组显效率略高于A、B两组。但三组差异无统计学意义（χ2=0.69，P>0.05），C组总有效率明显高于A、B两组，三组差异有统计学意义（χ2=10.08，P＜0.01）。 2.2不良反应B组有5例（16.7%），C组有2例（6.7%）出现轻微头痛、颜面潮红发热，但均能忍受，坚持到疗程结束。 3讨论
替米沙坦+苯磺酸左旋氨氯地平片治疗高血压的效果研究
替米沙坦+苯磺酸左旋氨氯地平片治疗高血压的效果研究 发表时间：2018-03-14T10:07:53.213Z 来源：《中国误诊学杂志》2017年第28期作者：王忠泽 [导读] 在高血压患者中，使用苯磺酸左旋氨氯地平联合替米沙坦进行治疗，能够有效提高疾病治疗效果，同时降低不良反应的发生率。天津市滨海新区大港太平社区卫生服务中心 300270 摘要：目的：研究在高血压疾病的治疗中使用苯磺酸左旋氨氯地平联合替米沙坦的效果.方法：我院在2016年6月~2017年6月间共收治高血压患者160例，将其按照治疗方法的不同分为两组，对照组患者使用苯磺酸左旋氨氯地平进行治疗，观察组患者同时加用替米沙坦，在治疗一个疗程之后对比两组患者的治疗效果以及不良反应发生情况。结果：观察组患者的治疗效果明显高于对照组，同时观察组患者的不良反应发生率也比对照组低，两组数据经检验P<0.05，具有显著差异。结论；在高血压患者中，使用苯磺酸左旋氨氯地平联合替米沙坦进行治疗，能够有效提高疾病治疗效果，同时降低不良反应的发生率。 关键词：替米沙坦；苯磺酸左旋氨氯地平；高血压 高血压疾病主要表现为动脉血压升高，其中会伴随不同程度的心脏和脑血管等疾病，而这类疾病的临床病死率较高[1]。临床资料显示，我国此类疾病的发病人数已达到了2亿人次。我院在进行此类疾病的研究中，对2016年6月~2017年6月入院接受治疗的150例高血压患者进行了分组对比试验研究，报道如下。 1.资料与方法 1.1一般资料 选取2016年6月~2017年6月入院接受治疗的高血压患者160例，将其分为两组，每组80例。观察组中，男42例，女38例，平均年龄（55.7±8.5）岁，平均病程（9.58±5.25）年，体重指数（25.96±2.85）kg/m，心率（76.26±7.25）次/min；对照组中，男39例，女41例，年龄（56.5±9.3）岁，病程（9.01±5.15）年，体重指数（25.26±2.83）kg/m，心率（75.92+7.55）次/min。两组患者一般资料比较无显著差异（P>0.05）。 1.2入选标准 本研究患者依据我国高血压防治指南中的相关标准进行筛选，其中对患者二维收缩压SBP≥140mmHg，舒张压DBP≥90mmHg，经三次检测后，选取平均值作为基本判断标准。所有患者均无心肌病、风心病等不良心脏疾病，排除患者存在的不良风心病以及先心病等。所有患者均无恶性肿瘤病变情况，且患者无药物禁忌病史。 1.3治疗方法 对照组给予苯磺酸左旋氨氯地平治疗（厂家：慧达药业集团（吉林）有限公司；批准文号：国药准字H19991083；规格：2.5mg），5mg/次，1次/d，8周为1个疗程，个体治疗差异因素遵循医嘱，保证治疗的安全性。观察组在对照组治疗的基础上，增加替米沙坦（厂家：勃林格殷格翰（德国）；批准文号：国药准字J20090089，规格：80mgx7片）进行治疗，初始使用剂量为40mg/d。每天早上起床服药，待达到正常标准后，可进行适当的药物剂量减少。实际用药标准遵循医嘱，保证治疗的安全性[2]。 1.4观察指标 疗效评价标准根据相关诊断标准评价患者疾病治疗的效果，①显效：舒张压或者收缩压有所下降，前者下降程度在20mmHg以上，后者下降程度在10mmHg以上，或者患者的血压经测量已经在正常范围之内；②有效：舒张压下降的程度在10mmHg以下，但是患者的血压经测量已经在正常范围之内，如果没有达到这条标准，但是舒张压达到了10~20mmHg的下降程度也纳入该等级，如果上述两条都不符合，那么患者收缩压下降的程度在30mmHg以上也可纳入；③无效：患者疾病经治疗，其血压均不符合上述评价标准。 1.5统计学方法 数据采用SPSS16.0统计学软件进行分析处理，计数资料用n/％表示，用检验，计量资料用±s表示，用t检验，以P<0.05为差异具有统计学意义。 2.结果 2.1两组患者疾病治疗效果 表1 两组患者疾病治疗效果对比（n、%） 研究结果显示，观察组患者总有效率为92.50%；对照组患者总有效率为81.25%，观察组患者治疗有效率明显高于对照组患者，两组经比较差异明显，具有统计学意义（P<0.05），见表1。 2.2两组患者不良反应发生率对比 在进行治疗的过程中，观察组患者仅有2例出现痛风的症状，所占比例为2.67%，对照组患者有4例出现低血钾症的情况，还有5例发生痛风，所占比例为12%，观察组明显低于对照组，两组差异明显（P<0.05）。 3.讨论 在老年人中，发生老年高血压的概率较高，相关数据显示其发病率已经接近50%，虽然年龄的增加也会导致血压出现升高的情况，但是如果升高程度明显，那么就会对患者的生活质量造成严重的影响，如果不进行及时有效的治疗则可能并发一些其他疾病，提高患者死亡的概率。所以一旦血压出现了不正常的升高现象，那么需要及时到正规医院进行诊疗，以免延误病情[3]。 苯磺酸左旋氨氯地平是一种长效二氢吡啶类药物，其能够有效地舒张血管平滑肌，对患者治疗有较好促进作用。这类药物在使用过程中，可以有效抗动脉粥样硬化，且促进一氧化碳的释放，从而起到对高血压疾病的缓解作用[4]。而相关的研究也指出，应用苯磺酸左旋氨
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