COZAAR XQ Losartan Potassium / Amlodipine 100mg / 5mg Film-Coated Tablet 1's
RXDRUG-DRP-5347-1pc
Discreet Packaging
FDA-registered Products
FDA-licensed Pharmacies
Indications/Uses
LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) is indicated for the treatment of essential hypertension.
LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) may be used in patients whose blood pressure is not adequately controlled on either monotherapy.
LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) may be used in patients whose blood pressure is not adequately controlled on either monotherapy.
Dosage/Direction for Use
The recommended dose of LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) is one tablet per day.
LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) may be administered with or without food. It is recommended to take LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) with water.
LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) may be administered with other antihypertensive agents.
Losartan is an effective treatment of hypertension in once daily doses of 50 mg to 100 mg while amlodipine is effective in doses of 5 mg to 10 mg as monotherapy. The maximum recommended dose of LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) is 5 mg/100 mg.
A patient whose blood pressure is not adequately controlled with losartan alone or amlodipine alone may be switched to combination therapy with LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ).
LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) 5 mg/50 mg may be administered in patients whose blood pressure is not adequately controlled with amlodipine 5 mg or losartan 50 mg alone.
LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) 5 mg/100 mg may be administered in patients whose blood pressure is not adequately controlled with losartan 100 mg or LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) 5 mg/50 mg.
A patient co-administered with losartan and amlodipine may be switched to LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) (fixed dose combination containing same dose of each ingredient) for compliance improvement.
Use in patients with renal impairment: No dosage adjustment is necessary in patients with mild renal impairment (i.e. creatinine clearance 20-50 ml/min). For patients with moderate to severe renal impairment (i.e. creatinine clearance <20 ml/min) or patients on dialysis, administration of LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) is not recommended.
Use in patients with intravascular volume depletion: For patients with intravascular volume-depletion (e.g., those treated with high-dose diuretics), a starting dose of 25 mg losartan once daily should be considered (see PRECAUTIONS). Since a 25 mg dose of losartan is not available with COZAAR XQ, this dose should be achieved with losartan monotherapy.
Use in patients with hepatic impairment: In cases where a lower dose of losartan (i.e. 25 mg once daily) is required for patients with a history of hepatic impairment, administration of LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) is not recommended.
Use in the elderly: Because of decreased clearance in the elderly, amlodipine therapy should usually be initiated at 2.5 mg daily. Since a 2.5 mg dose of amlodipine is not available with LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ), this dose should be achieved with amlodipine monotherapy.
Use in adolescents and children: Since safety and efficacy of LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) in children ≤18 years of age has not been established, administration of LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) is not recommended.
LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) may be administered with or without food. It is recommended to take LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) with water.
LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) may be administered with other antihypertensive agents.
Losartan is an effective treatment of hypertension in once daily doses of 50 mg to 100 mg while amlodipine is effective in doses of 5 mg to 10 mg as monotherapy. The maximum recommended dose of LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) is 5 mg/100 mg.
A patient whose blood pressure is not adequately controlled with losartan alone or amlodipine alone may be switched to combination therapy with LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ).
LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) 5 mg/50 mg may be administered in patients whose blood pressure is not adequately controlled with amlodipine 5 mg or losartan 50 mg alone.
LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) 5 mg/100 mg may be administered in patients whose blood pressure is not adequately controlled with losartan 100 mg or LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) 5 mg/50 mg.
A patient co-administered with losartan and amlodipine may be switched to LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) (fixed dose combination containing same dose of each ingredient) for compliance improvement.
Use in patients with renal impairment: No dosage adjustment is necessary in patients with mild renal impairment (i.e. creatinine clearance 20-50 ml/min). For patients with moderate to severe renal impairment (i.e. creatinine clearance <20 ml/min) or patients on dialysis, administration of LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) is not recommended.
Use in patients with intravascular volume depletion: For patients with intravascular volume-depletion (e.g., those treated with high-dose diuretics), a starting dose of 25 mg losartan once daily should be considered (see PRECAUTIONS). Since a 25 mg dose of losartan is not available with COZAAR XQ, this dose should be achieved with losartan monotherapy.
Use in patients with hepatic impairment: In cases where a lower dose of losartan (i.e. 25 mg once daily) is required for patients with a history of hepatic impairment, administration of LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) is not recommended.
Use in the elderly: Because of decreased clearance in the elderly, amlodipine therapy should usually be initiated at 2.5 mg daily. Since a 2.5 mg dose of amlodipine is not available with LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ), this dose should be achieved with amlodipine monotherapy.
Use in adolescents and children: Since safety and efficacy of LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) in children ≤18 years of age has not been established, administration of LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) is not recommended.
Overdosage
LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ): There are no data available in regard to overdosage of LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) in humans. The overdose on each ingredient of amlodipine and losartan are described.
Losartan: Limited data are available in regard to overdosage in humans. The most likely manifestation of overdosage would be hypotension and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be instituted.
Neither losartan nor the active metabolite can be removed by hemodialysis.
Amlodipine: Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly a reflex tachycardia. In humans, experience with intentional overdosage of amlodipine is limited.
Single oral doses of amlodipine maleate equivalent to 40 mg amlodipine/kg and 100 mg amlodipine/kg in mice and rats, respectively, caused deaths. Single oral amlodipine maleate doses equivalent to 4 or more mg amlodipine/kg or higher in dogs (11 or more times the maximum recommended human dose on a mg/m2 basis) caused a marked peripheral vasodilation and hypotension.
If massive overdose should occur, initiate active cardiac and respiratory monitoring. Frequent blood pressure measurements are essential. Should hypotension occur, provide cardiovascular support including elevation of the extremities and the judicious administration of fluids. If hypotension remains unresponsive to these conservative measures, consider administration of vasopressors (such as phenylephrine) with attention to circulating volume and urine output. As amlodipine is highly protein bound, hemodialysis is not likely to be of benefit.
Losartan: Limited data are available in regard to overdosage in humans. The most likely manifestation of overdosage would be hypotension and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be instituted.
Neither losartan nor the active metabolite can be removed by hemodialysis.
Amlodipine: Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly a reflex tachycardia. In humans, experience with intentional overdosage of amlodipine is limited.
Single oral doses of amlodipine maleate equivalent to 40 mg amlodipine/kg and 100 mg amlodipine/kg in mice and rats, respectively, caused deaths. Single oral amlodipine maleate doses equivalent to 4 or more mg amlodipine/kg or higher in dogs (11 or more times the maximum recommended human dose on a mg/m2 basis) caused a marked peripheral vasodilation and hypotension.
If massive overdose should occur, initiate active cardiac and respiratory monitoring. Frequent blood pressure measurements are essential. Should hypotension occur, provide cardiovascular support including elevation of the extremities and the judicious administration of fluids. If hypotension remains unresponsive to these conservative measures, consider administration of vasopressors (such as phenylephrine) with attention to circulating volume and urine output. As amlodipine is highly protein bound, hemodialysis is not likely to be of benefit.
Administration
May be taken with or without food.
Contraindications
LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) is contraindicated in patients who are hypersensitive to any component of this product.
LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) should not be administered with aliskiren in patients with diabetes (see INTERACTIONS).
LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) should not be administered with aliskiren in patients with diabetes (see INTERACTIONS).
Special Precautions
LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ): Hypotension: In patients who are intravascularly volume-depleted (e.g., those treated with high-dose diuretics) or with severe aortic stenosis, symptomatic hypotension may occur. Intravascular volume depletion should be corrected prior to administration of LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ), or a lower starting dose should be used (see DOSAGE & ADMINISTRATION). Because of the gradual onset of action, acute hypotension is unlikely.
Liver function impairment: Based on pharmacokinetic data which demonstrate significantly increased plasma concentrations of losartan in cirrhotic patients, a lower dose of losartan should be considered for patients with a history of hepatic impairment (see DOSAGE & ADMINISTRATION and PHARMACOLOGY: PHARMACOKINETICS under ACTIONS).
Because amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t½) is 56 hours in patients with impaired hepatic function, titrate slowly when administering amlodipine to patients with severe hepatic impairment.
Losartan: Fetal Toxicity: Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) as soon as possible. See USE IN PREGNANCY & LACTATION.
Hypersensitivity: Angioedema. (See ADVERSE REACTIONS.)
Electrolyte/Fluid Imbalance: Electrolyte imbalances are common in patients with renal impairment, with or without diabetes, and should be addressed. In a clinical study conducted in type 2 diabetic patients with proteinuria, the incidence of hyperkalemia was higher in the group treated with losartan as compared to the placebo group; however, few patients discontinued therapy due to hyperkalemia (see ADVERSE REACTIONS).
Concomitant use of other drugs that may increase serum potassium may lead to hyperkalemia (see INTERACTIONS).
Renal Function Impairment: As a consequence of inhibiting the renin-angiotensin system, changes in renal function including renal failure have been reported in susceptible individuals; these changes in renal function may be reversible upon discontinuation of therapy.
Other drugs that affect the renin-angiotensin system may increase blood urea and serum creatinine in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney. Similar effects have been reported with losartan; these changes in renal function may be reversible upon discontinuation of therapy.
Amlodipine: Increased Angina or Myocardial Infarction: 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.
Use in Children: Since safety and efficacy of LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) in children ≤18 years of age has not been established, administration of LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) is not recommended.
Neonates with a history of in utero exposure to LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ): If oliguria or hypotension occur, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.
Use in Elderly: In clinical studies there was no age-related difference in the efficacy or safety profile of losartan.
Because of decreased clearance of amlodipine in the elderly, with a resulting increase of AUC of approximately 40-60% amlodipine therapy should usually be initiated at 2.5 mg daily. Since a 2.5 mg dose of amlodipine is not available with LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ), this dose should be achieved with amlodipine monotherapy.
Liver function impairment: Based on pharmacokinetic data which demonstrate significantly increased plasma concentrations of losartan in cirrhotic patients, a lower dose of losartan should be considered for patients with a history of hepatic impairment (see DOSAGE & ADMINISTRATION and PHARMACOLOGY: PHARMACOKINETICS under ACTIONS).
Because amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t½) is 56 hours in patients with impaired hepatic function, titrate slowly when administering amlodipine to patients with severe hepatic impairment.
Losartan: Fetal Toxicity: Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) as soon as possible. See USE IN PREGNANCY & LACTATION.
Hypersensitivity: Angioedema. (See ADVERSE REACTIONS.)
Electrolyte/Fluid Imbalance: Electrolyte imbalances are common in patients with renal impairment, with or without diabetes, and should be addressed. In a clinical study conducted in type 2 diabetic patients with proteinuria, the incidence of hyperkalemia was higher in the group treated with losartan as compared to the placebo group; however, few patients discontinued therapy due to hyperkalemia (see ADVERSE REACTIONS).
Concomitant use of other drugs that may increase serum potassium may lead to hyperkalemia (see INTERACTIONS).
Renal Function Impairment: As a consequence of inhibiting the renin-angiotensin system, changes in renal function including renal failure have been reported in susceptible individuals; these changes in renal function may be reversible upon discontinuation of therapy.
Other drugs that affect the renin-angiotensin system may increase blood urea and serum creatinine in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney. Similar effects have been reported with losartan; these changes in renal function may be reversible upon discontinuation of therapy.
Amlodipine: Increased Angina or Myocardial Infarction: 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.
Use in Children: Since safety and efficacy of LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) in children ≤18 years of age has not been established, administration of LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) is not recommended.
Neonates with a history of in utero exposure to LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ): If oliguria or hypotension occur, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.
Use in Elderly: In clinical studies there was no age-related difference in the efficacy or safety profile of losartan.
Because of decreased clearance of amlodipine in the elderly, with a resulting increase of AUC of approximately 40-60% amlodipine therapy should usually be initiated at 2.5 mg daily. Since a 2.5 mg dose of amlodipine is not available with LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ), this dose should be achieved with amlodipine monotherapy.
Use In Pregnancy & Lactation
Pregnancy: Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. When pregnancy is detected, discontinue LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) as soon as possible.
Although there is no experience with the use of LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) in pregnant women, animal studies with losartan potassium have demonstrated fetal and neonatal injury and death, the mechanism of which is believed to be pharmacologically mediated through effects on the renin-angiotensin system. In humans, fetal renal perfusion, which is dependent upon the development of the renin-angiotensin system, begins in the second trimester; thus, risk to the fetus increases if LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) is administered during the second or third trimesters of pregnancy.
Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) as soon as possible.
These adverse outcomes are usually associated with the use of these drugs in the second and third trimesters of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.
In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ), unless it is considered life-saving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) for hypotension, oliguria, and hyperkalemia.
There are no adequate and well-controlled studies of amlodipine in pregnant women.
Nursing Mothers: It is not known whether losartan or amlodipine is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Although there is no experience with the use of LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) in pregnant women, animal studies with losartan potassium have demonstrated fetal and neonatal injury and death, the mechanism of which is believed to be pharmacologically mediated through effects on the renin-angiotensin system. In humans, fetal renal perfusion, which is dependent upon the development of the renin-angiotensin system, begins in the second trimester; thus, risk to the fetus increases if LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) is administered during the second or third trimesters of pregnancy.
Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) as soon as possible.
These adverse outcomes are usually associated with the use of these drugs in the second and third trimesters of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.
In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ), unless it is considered life-saving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) for hypotension, oliguria, and hyperkalemia.
There are no adequate and well-controlled studies of amlodipine in pregnant women.
Nursing Mothers: It is not known whether losartan or amlodipine is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Adverse Reactions
LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ): The safety of LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) has been evaluated in 325 patients treated with amlodipine/losartan combination therapy among 646 essential hypertension patients in 3 clinical trials (study 201, study 301 and study 302) for 8 weeks. Adverse reactions have been ranked under headings of frequency using the following convention: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); very rare (<1/10,000). (See Table 1.)
Additional information for each active ingredient: The following adverse reactions have been reported with the components of LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ).
Losartan: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Losartan has been found to be generally well-tolerated in controlled clinical trials for hypertension; side effects have usually been mild and transient in nature and have not required discontinuation of therapy. The overall incidence of side effects reported with losartan was comparable to placebo.
In controlled clinical trials for essential hypertension, dizziness was the only side effect reported as drug related that occurred with an incidence greater than placebo in one percent or more of patients treated with losartan. In addition, dose-related orthostatic effects were seen in less than one percent of patients. Rarely, rash was reported, although the incidence in controlled clinical trials was less than placebo.
In these double-blind controlled clinical trials for essential hypertension, the following adverse experiences reported with losartan occurred in ≥1 percent of patients, regardless of drug relationship: See Table 2.
Losartan: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Losartan has been found to be generally well-tolerated in controlled clinical trials for hypertension; side effects have usually been mild and transient in nature and have not required discontinuation of therapy. The overall incidence of side effects reported with losartan was comparable to placebo.
In controlled clinical trials for essential hypertension, dizziness was the only side effect reported as drug related that occurred with an incidence greater than placebo in one percent or more of patients treated with losartan. In addition, dose-related orthostatic effects were seen in less than one percent of patients. Rarely, rash was reported, although the incidence in controlled clinical trials was less than placebo.
In these double-blind controlled clinical trials for essential hypertension, the following adverse experiences reported with losartan occurred in ≥1 percent of patients, regardless of drug relationship: See Table 2.
Losartan was generally well-tolerated in a controlled clinical trial in hypertensive patients with left ventricular hypertrophy. The most common drug-related side effects were dizziness, asthenia/fatigue, and vertigo.
In that study, among patients without diabetes at baseline, there was a lower incidence of new onset diabetes mellitus with losartan as compared to atenolol (242 patients versus 320 patients, respectively, p<0.001). Because there was no placebo group included in the study, it is not known if this represents a beneficial effect of losartan or an adverse effect of atenolol.
Losartan was generally well-tolerated in a controlled clinical trial in type 2 diabetic patients with proteinuria. The most common drug-related side effects were asthenia/fatigue, dizziness, hypotension and hyperkalemia (see Hypotension and Electrolyte/Fluid Imbalance under PRECAUTIONS).
The following additional adverse reactions have been reported in post-marketing experience: Hypersensitivity: Anaphylactic reactions, angioedema including swelling of the larynx and glottis causing airway obstruction and/or swelling of the face, lips, pharynx and/or tongue has been reported rarely in patients treated with losartan; some of these patients previously experienced angioedema with other drugs including ACE inhibitors. Vasculitis, including Henoch-Schoenlein purpura, has been reported rarely.
Gastrointestinal: Hepatitis (reported rarely), liver function abnormalities, vomiting.
General disorders and administration site conditions: Malaise.
Hematologic: Anemia, thrombocytopenia (reported rarely).
Musculoskeletal: Myalgia, arthralgia.
Nervous System/Psychiatric: Migraine, dysgeusia.
Reproductive system and breast disorders: Erectile dysfunction/impotence.
Respiratory: Cough.
Skin: Urticaria, pruritus, erythroderma, photosensitivity.
Amlodipine besylate: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Amlodipine besylate has been evaluated for safety in more than 11,000 patients in worldwide clinical trials. In general, treatment with amlodipine besylate was well-tolerated at doses up to 10 mg daily. Most adverse reactions reported during therapy with amlodipine besylate were of mild or moderate severity. In controlled clinical trials directly comparing amlodipine besylate (N=1730) at doses up to 10 mg to placebo (N=1250), discontinuation of amlodipine besylate due to adverse reactions was required in only about 1.5% of patients and was not significantly different from placebo (about 1%). The most common side effects are headache and edema. The incidence (%) of side effects that occurred in a dose related manner are as follows: See Table 3.
In that study, among patients without diabetes at baseline, there was a lower incidence of new onset diabetes mellitus with losartan as compared to atenolol (242 patients versus 320 patients, respectively, p<0.001). Because there was no placebo group included in the study, it is not known if this represents a beneficial effect of losartan or an adverse effect of atenolol.
Losartan was generally well-tolerated in a controlled clinical trial in type 2 diabetic patients with proteinuria. The most common drug-related side effects were asthenia/fatigue, dizziness, hypotension and hyperkalemia (see Hypotension and Electrolyte/Fluid Imbalance under PRECAUTIONS).
The following additional adverse reactions have been reported in post-marketing experience: Hypersensitivity: Anaphylactic reactions, angioedema including swelling of the larynx and glottis causing airway obstruction and/or swelling of the face, lips, pharynx and/or tongue has been reported rarely in patients treated with losartan; some of these patients previously experienced angioedema with other drugs including ACE inhibitors. Vasculitis, including Henoch-Schoenlein purpura, has been reported rarely.
Gastrointestinal: Hepatitis (reported rarely), liver function abnormalities, vomiting.
General disorders and administration site conditions: Malaise.
Hematologic: Anemia, thrombocytopenia (reported rarely).
Musculoskeletal: Myalgia, arthralgia.
Nervous System/Psychiatric: Migraine, dysgeusia.
Reproductive system and breast disorders: Erectile dysfunction/impotence.
Respiratory: Cough.
Skin: Urticaria, pruritus, erythroderma, photosensitivity.
Amlodipine besylate: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Amlodipine besylate has been evaluated for safety in more than 11,000 patients in worldwide clinical trials. In general, treatment with amlodipine besylate was well-tolerated at doses up to 10 mg daily. Most adverse reactions reported during therapy with amlodipine besylate were of mild or moderate severity. In controlled clinical trials directly comparing amlodipine besylate (N=1730) at doses up to 10 mg to placebo (N=1250), discontinuation of amlodipine besylate due to adverse reactions was required in only about 1.5% of patients and was not significantly different from placebo (about 1%). The most common side effects are headache and edema. The incidence (%) of side effects that occurred in a dose related manner are as follows: See Table 3.
Other adverse experiences that were not clearly dose related but were reported with an incidence greater than 1.0% in placebo-controlled clinical trials include the following: See Table 4.
For several adverse experiences that appear to be drug and dose related, there was a greater incidence in women than men associated with amlodipine besylate treatment as shown in the following table: See Table 5.
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, dyspepsia1, dysphagia, diarrhea, flatulence, pancreatitis, vomiting, gingival hyperplasia.
General: allergic reaction, asthenia1, back pain, hot flushes, malaise, pain, rigors, weight gain, weight decrease.
Musculoskeletal System: arthralgia, arthrosis, muscle cramps1, myalgia.
Psychiatric: sexual dysfunction (male1 and female), insomnia, nervousness, depression, abnormal dreams, anxiety, depersonalization.
Respiratory System: dyspnea1, epistaxis.
Skin and Appendages: angioedema, erythema multiforme, pruritus1, rash1, 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.
1 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.
The following additional adverse reactions have been reported in post-marketing experience: Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
The following postmarketing event has been reported infrequently where a causal relationship is uncertain: gynecomastia. In postmarketing experience, 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 besylate.
Amlodipine besylate 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.
Laboratory Test Findings: LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ): Slowed heart rate was observed in some patients 8 weeks after administration of losartan/amlodipine, but the change in heart rate was not clinically significant.
Increased blood creatinine and increased hepatic enzyme were reported in some patients but specific laboratory monitoring is not required.
Losartan: In controlled clinical trials for essential hypertension, clinically important changes in standard laboratory parameters were rarely associated with administration of COZAAR. Hyperkalemia (serum potassium >5.5 mEq/L) occurred in 1.5% of patients in the hypertension clinical trials. In a clinical study conducted in type 2 diabetic patients with proteinuria, 9.9% of patients treated with COZAAR and 3.4% of patients treated with placebo developed hyperkalemia (see Hypotension and Electrolyte/Fluid Imbalance under PRECAUTIONS). Elevations of ALT occurred rarely and usually resolved upon discontinuation of therapy.
Amlodipine: Amlodipine therapy 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.
Central and Peripheral Nervous System: hypoesthesia, neuropathy peripheral, paresthesia, tremor, vertigo.
Gastrointestinal: anorexia, constipation, dyspepsia1, dysphagia, diarrhea, flatulence, pancreatitis, vomiting, gingival hyperplasia.
General: allergic reaction, asthenia1, back pain, hot flushes, malaise, pain, rigors, weight gain, weight decrease.
Musculoskeletal System: arthralgia, arthrosis, muscle cramps1, myalgia.
Psychiatric: sexual dysfunction (male1 and female), insomnia, nervousness, depression, abnormal dreams, anxiety, depersonalization.
Respiratory System: dyspnea1, epistaxis.
Skin and Appendages: angioedema, erythema multiforme, pruritus1, rash1, 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.
1 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.
The following additional adverse reactions have been reported in post-marketing experience: Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
The following postmarketing event has been reported infrequently where a causal relationship is uncertain: gynecomastia. In postmarketing experience, 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 besylate.
Amlodipine besylate 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.
Laboratory Test Findings: LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ): Slowed heart rate was observed in some patients 8 weeks after administration of losartan/amlodipine, but the change in heart rate was not clinically significant.
Increased blood creatinine and increased hepatic enzyme were reported in some patients but specific laboratory monitoring is not required.
Losartan: In controlled clinical trials for essential hypertension, clinically important changes in standard laboratory parameters were rarely associated with administration of COZAAR. Hyperkalemia (serum potassium >5.5 mEq/L) occurred in 1.5% of patients in the hypertension clinical trials. In a clinical study conducted in type 2 diabetic patients with proteinuria, 9.9% of patients treated with COZAAR and 3.4% of patients treated with placebo developed hyperkalemia (see Hypotension and Electrolyte/Fluid Imbalance under PRECAUTIONS). Elevations of ALT occurred rarely and usually resolved upon discontinuation of therapy.
Amlodipine: Amlodipine therapy 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.
Drug Interactions
LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ): No drug interaction studies have been conducted with LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) and other drugs, although studies have been conducted with the individual losartan and amlodipine components, as described as follows.
Losartan: In clinical pharmacokinetic trials, no drug interactions of clinical significance have been identified with hydrochlorothiazide, digoxin, warfarin, cimetidine, phenobarbital, ketoconazole, and erythromycin. Rifampin and fluconazole have been reported to reduce levels of active metabolite. The clinical consequences of these interactions have not been evaluated.
As with other drugs that block angiotensin II or its effects, concomitant use of potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, salt substitutes containing potassium, or other drugs that may increase serum potassium (e.g., trimethoprim-containing products) may lead to increases in serum potassium.
As with other drugs which affect the excretion of sodium, lithium excretion may be reduced. Therefore, serum lithium levels should be monitored carefully if lithium salts are to be co-administered with angiotensin II receptor antagonists.
Non-steroidal anti-inflammatory drugs (NSAIDs) including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors) may reduce the effect of diuretics and other antihypertensive drugs. Therefore, the antihypertensive effect of angiotensin II receptor antagonists or ACE inhibitors may be attenuated by NSAIDs including selective COX-2 inhibitors.
In some patients with compromised renal function (e.g., elderly patients or patients who are volume-depleted, including those on diuretic therapy) who are being treated with non-steroidal anti-inflammatory drugs, including selective cyclooxygenase-2 inhibitors, the co-administration of angiotensin II receptor antagonists or ACE inhibitors may result in a further deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Therefore, the combination should be administered with caution in patients with compromised renal function.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS) with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, syncope, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function, and electrolytes in patients on LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) and other agents that affect the RAAS. Do not co-administer aliskiren with LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) in patients with diabetes. Avoid use of aliskiren with COZAAR XQ in patients with renal impairment (GFR <60 ml/min).
Amlodipine: In Vitro Data: In vitro data indicate that amlodipine has no effect on the human plasma protein binding of digoxin, phenytoin, warfarin, and indomethacin.
Cimetidine: Co-administration of amlodipine with cimetidine did not alter the pharmacokinetics of amlodipine.
Grapefruit Juice: Co-administration of 240 mL of grapefruit juice with a single oral dose of amlodipine 10 mg in 20 healthy volunteers had no significant effect on the pharmacokinetics of amlodipine.
Magnesium and Aluminum Hydroxide Antacid: Co-administration of a magnesium and aluminum hydroxide antacid with a single dose of amlodipine had no significant effect on the pharmacokinetics of amlodipine.
Sildenafil: A single 100 mg dose of sildenafil in subjects with essential hypertension had no effect on the pharmacokinetic parameters of amlodipine. When amlodipine and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect.
Atorvastatin: Co-administration of multiple 10 mg doses of amlodipine with 80 mg of atorvastatin resulted in no significant change in the steady-state pharmacokinetic parameters of atorvastatin.
Digoxin: Co-administration of amlodipine with digoxin did not change serum digoxin levels or digoxin renal clearance in normal volunteers.
Ethanol (Alcohol): Single and multiple 10 mg doses of amlodipine had no significant effect on the pharmacokinetics of ethanol.
Warfarin: Co-administration of amlodipine with warfarin did not change the warfarin prothrombin response time.
CYP3A4 Inhibitors: Co-administration of a 180 mg daily dose of diltiazem with 5 mg amlodipine in elderly hypertensive patients resulted in a 1.6-fold increase in amlodipine systemic exposure. Erythromycin co-administration in healthy volunteers did not significantly change amlodipine systemic exposure. However, strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, ritonavir) may increase the plasma concentrations of amlodipine to a greater extent. Monitor for symptoms of hypotension and edema when amlodipine is co-administered with CYP3A4 inhibitors.
CYP3A4 Inducers: No information is available on the quantitative effects of CYP3A4 inducers on amlodipine. Patients should be monitored for adequate clinical effect when amlodipine is co-administered with CYP3A4 inducers.
Drug/Laboratory Test Interactions: None known.
Losartan: In clinical pharmacokinetic trials, no drug interactions of clinical significance have been identified with hydrochlorothiazide, digoxin, warfarin, cimetidine, phenobarbital, ketoconazole, and erythromycin. Rifampin and fluconazole have been reported to reduce levels of active metabolite. The clinical consequences of these interactions have not been evaluated.
As with other drugs that block angiotensin II or its effects, concomitant use of potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, salt substitutes containing potassium, or other drugs that may increase serum potassium (e.g., trimethoprim-containing products) may lead to increases in serum potassium.
As with other drugs which affect the excretion of sodium, lithium excretion may be reduced. Therefore, serum lithium levels should be monitored carefully if lithium salts are to be co-administered with angiotensin II receptor antagonists.
Non-steroidal anti-inflammatory drugs (NSAIDs) including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors) may reduce the effect of diuretics and other antihypertensive drugs. Therefore, the antihypertensive effect of angiotensin II receptor antagonists or ACE inhibitors may be attenuated by NSAIDs including selective COX-2 inhibitors.
In some patients with compromised renal function (e.g., elderly patients or patients who are volume-depleted, including those on diuretic therapy) who are being treated with non-steroidal anti-inflammatory drugs, including selective cyclooxygenase-2 inhibitors, the co-administration of angiotensin II receptor antagonists or ACE inhibitors may result in a further deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Therefore, the combination should be administered with caution in patients with compromised renal function.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS) with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, syncope, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function, and electrolytes in patients on LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) and other agents that affect the RAAS. Do not co-administer aliskiren with LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) in patients with diabetes. Avoid use of aliskiren with COZAAR XQ in patients with renal impairment (GFR <60 ml/min).
Amlodipine: In Vitro Data: In vitro data indicate that amlodipine has no effect on the human plasma protein binding of digoxin, phenytoin, warfarin, and indomethacin.
Cimetidine: Co-administration of amlodipine with cimetidine did not alter the pharmacokinetics of amlodipine.
Grapefruit Juice: Co-administration of 240 mL of grapefruit juice with a single oral dose of amlodipine 10 mg in 20 healthy volunteers had no significant effect on the pharmacokinetics of amlodipine.
Magnesium and Aluminum Hydroxide Antacid: Co-administration of a magnesium and aluminum hydroxide antacid with a single dose of amlodipine had no significant effect on the pharmacokinetics of amlodipine.
Sildenafil: A single 100 mg dose of sildenafil in subjects with essential hypertension had no effect on the pharmacokinetic parameters of amlodipine. When amlodipine and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect.
Atorvastatin: Co-administration of multiple 10 mg doses of amlodipine with 80 mg of atorvastatin resulted in no significant change in the steady-state pharmacokinetic parameters of atorvastatin.
Digoxin: Co-administration of amlodipine with digoxin did not change serum digoxin levels or digoxin renal clearance in normal volunteers.
Ethanol (Alcohol): Single and multiple 10 mg doses of amlodipine had no significant effect on the pharmacokinetics of ethanol.
Warfarin: Co-administration of amlodipine with warfarin did not change the warfarin prothrombin response time.
CYP3A4 Inhibitors: Co-administration of a 180 mg daily dose of diltiazem with 5 mg amlodipine in elderly hypertensive patients resulted in a 1.6-fold increase in amlodipine systemic exposure. Erythromycin co-administration in healthy volunteers did not significantly change amlodipine systemic exposure. However, strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, ritonavir) may increase the plasma concentrations of amlodipine to a greater extent. Monitor for symptoms of hypotension and edema when amlodipine is co-administered with CYP3A4 inhibitors.
CYP3A4 Inducers: No information is available on the quantitative effects of CYP3A4 inducers on amlodipine. Patients should be monitored for adequate clinical effect when amlodipine is co-administered with CYP3A4 inducers.
Drug/Laboratory Test Interactions: None known.
Storage
Store below 30°C. Protect from moisture.
Action
Pharmacology: Pharmacodynamics: LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ): LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) has been shown to be effective in lowering blood pressure. Both losartan and amlodipine lower blood pressure by reducing peripheral resistance. Calcium influx blockade and reduction of angiotensin II vasoconstriction are complementary mechanisms.
Losartan: Losartan inhibits systolic and diastolic pressor responses to angiotensin II infusions. At peak, 100 mg of losartan potassium inhibits these responses by approximately 85%; 24 hours after single and multiple-dose administration, inhibition is about 26-39%.
During losartan administration, removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity. Increases in plasma renin activity lead to increases in angiotensin II in plasma. During chronic (6 weeks) treatment of hypertensive patients with 100 mg/day losartan, approximately 2-3 fold increases of plasma angiotensin II were observed at time of peak plasma drug concentrations. In some patients, greater increases were observed, particularly during short term (2 weeks) treatment. However, antihypertensive activity and suppression of plasma aldosterone concentration were apparent at 2 and 6 weeks, indicating effective angiotensin II receptor blockade. After discontinuation of losartan, plasma renin activity and angiotensin II levels declined to untreated levels within 3 days.
Since losartan is a specific antagonist of the angiotensin II receptor type AT1, it does not inhibit ACE (kininase II), the enzyme that degrades bradykinin. In a study which compared the effects of 20 mg and 100 mg of losartan potassium and an ACE inhibitor on responses to angiotensin I, angiotensin II and bradykinin, losartan was shown to block responses to angiotensin I and angiotensin II without affecting responses to bradykinin. This finding is consistent with losartan's specific mechanism of action. In contrast, the ACE inhibitor was shown to block responses to angiotensin I and enhance responses to bradykinin without altering the response to angiotensin II, thus providing a pharmacodynamic distinction between losartan and ACE inhibitors.
Plasma concentrations of losartan and its active metabolite and the antihypertensive effect of losartan increase with increasing dose. Since losartan and its active metabolite are both angiotensin II receptor antagonists, they both contribute to the antihypertensive effect.
In a single-dose study in normal males, the administration of 100 mg of losartan potassium, under dietary high- and low-salt conditions, did not alter glomerular filtration rate, effective renal plasma flow or filtration fraction. Losartan had a natriuretic effect which was more pronounced on a low-salt diet and did not appear to be related to inhibition of early proximal reabsorption of sodium. Losartan also caused a transient increase in urinary uric acid excretion.
In nondiabetic hypertensive patients with proteinuria (≥2 g/24 hours) treated for 8 weeks, the administration of losartan potassium 50 mg titrated to 100 mg significantly reduced proteinuria by 42%. Fractional excretion of albumin and IgG also was significantly reduced. In these patients, losartan maintained glomerular filtration rate and reduced filtration fraction.
In postmenopausal hypertensive women treated for 4 weeks, 50 mg of losartan potassium had no effect on renal or systemic prostaglandin levels.
Losartan has no effect on autonomic reflexes and no sustained effect on plasma norepinephrine.
Losartan potassium, administered in doses of up to 150 mg once daily, did not cause clinically important changes in fasting triglycerides, total cholesterol or HDL-cholesterol in patients with hypertension. The same doses of losartan had no effect on fasting glucose levels.
Generally losartan caused a decrease in serum uric acid (usually <0.4 mg/dL) which was persistent in chronic therapy. In controlled clinical trials in hypertensive patients, no patients were discontinued due to increases in serum creatinine or serum potassium.
In a 12-week, parallel-design study in patients with left ventricular failure (New York Heart Association Functional Classes II-IV), most of whom were receiving diuretics and/or digitalis, losartan potassium administered in once-daily doses of 2.5, 10, 25 and 50 mg was compared to placebo. The 25-mg and 50-mg doses produced positive hemodynamic and neurohormonal effects which were maintained for the length of the study. Hemodynamic responses were characterized by an increase in cardiac index and decreases in: pulmonary capillary wedge pressure, systemic vascular resistance, mean systemic arterial pressure and heart rate. The occurrence of hypotension was dose related in these heart failure patients. Neurohormonal results were characterized by a reduction in circulating levels of aldosterone and norepinephrine.
Amlodipine: Hemodynamics: 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 oral 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 pressures (+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.
Electrophysiologic 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 on 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.
Pharmacokinetics: Absorption: Losartan: Following oral administration, losartan is well absorbed and undergoes first-pass metabolism, forming an active carboxylic acid metabolite and other inactive metabolites. The systemic bioavailability of losartan tablets is approximately 33%. Mean peak concentrations of losartan and its active metabolite are reached in 1 hour and in 3-4 hours, respectively. There was no clinically significant effect on the plasma concentration profile of losartan when the drug was administered with a standardized meal.
Amlodipine: After oral administration of therapeutic doses of amlodipine, absorption produces peak plasma concentrations between 6 and 12 hours. Absolute bioavailability has been estimated to be between 64 and 90%. The bioavailability of amlodipine is not altered by the presence of food.
Distribution: Losartan: Both losartan and its active metabolite are ≥99% bound to plasma proteins, primarily albumin. The volume of distribution of losartan is 34 liters. Studies in rats indicate that losartan crosses the blood-brain barrier poorly, if at all.
Amlodipine: Ex vivo studies have shown that approximately 93% of the circulating drug is bound to plasma proteins in hypertensive patients.
Metabolism: Losartan: About 14% of an intravenously- or orally-administered dose of losartan is converted to its active metabolite. Following oral and intravenous administration of 14C-labeled losartan potassium, circulating plasma radioactivity primarily is attributed to losartan and its active metabolite. Minimal conversion of losartan to its active metabolite was seen in about one percent of individuals studied.
In addition to the active metabolite, inactive metabolites are formed, including two major metabolites formed by hydroxylation of the butyl side chain and a minor metabolite, an N-2 tetrazole glucuronide.
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.
Elimination: Losartan: Plasma clearance of losartan and its active metabolite is about 600 mL/min and 50 mL/min, respectively. Renal clearance of losartan and its active metabolite is about 74 mL/min and 26 mL/min, respectively. When losartan is administered orally, about 4% of the dose is excreted unchanged in the urine, and about 6% of the dose is excreted in the urine as active metabolite. The pharmacokinetics of losartan and its active metabolite are linear with oral losartan potassium doses up to 200 mg.
Following oral administration, plasma concentrations of losartan and its active metabolite decline polyexponentially with a terminal half-life of about 2 hours and 6-9 hours, respectively. During once-daily dosing with 100 mg, neither losartan nor its active metabolite accumulates significantly in plasma.
Both biliary and urinary excretion contribute to the elimination of losartan and its metabolites. Following an oral dose of 14C-labeled losartan in man, about 35% of radioactivity is recovered in the urine and 58% in the feces. Following an intravenous dose of 14C-labeled losartan in man, about 43% of radioactivity is recovered in the urine and 50% in the feces.
Amlodipine: Elimination from the plasma is biphasic with a terminal elimination half-life of about 30-50 hours. Steady-state plasma levels of amlodipine are reached after 7 to 8 days of consecutive daily dosing.
Characteristics in Patients: LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ): LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) has not been studied in any special populations, due to the well known nature of losartan and amlodipine. Caution is advised for losartan in renal and hepatic impairment, and is contraindicated in breast feeding. No formal studies have been performed in either the elderly or children. For amlodipine caution is advised in hepatic impairment, and amlodipine is contraindicated in unstable cardiovascular disease and pregnancy/lactation.
Losartan: The plasma concentrations of losartan and its active metabolite observed in elderly male hypertensives are not significantly different from those observed in young male hypertensives.
Plasma concentrations of losartan were up to 2-fold higher in female hypertensives as compared to male hypertensives. Concentrations of the active metabolite were not different in males and females. This apparent pharmacokinetic difference is not judged to be of clinical significance.
Following oral administration in patients with mild to moderate alcoholic cirrhosis of the liver, plasma concentrations of losartan and its active metabolite were, respectively, 5-fold and 1.7-fold greater than those seen in young male volunteers.
Plasma concentrations of losartan are not altered in patients with creatinine clearance above 10 mL/min. Compared to patients with normal renal function, the AUC for losartan is approximately 2-fold greater in hemodialysis patients. Plasma concentrations of the active metabolite are not altered in patients with renal impairment or in hemodialysis patients. Neither losartan nor the active metabolite can be removed by hemodialysis.
Amlodipine: The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. Patients with renal failure may therefore receive the usual initial dose.
Elderly patients and patients with hepatic insufficiency have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40-60%, and a lower initial dose may be required. A similar increase in AUC was observed in patients with moderate to severe heart failure.
Sixty-two hypertensive patients aged 6 to 17 years received doses of amlodipine between 1.25 mg and 20 mg. Weight-adjusted clearance and volume of distribution were similar to values in adults.
Losartan: Losartan inhibits systolic and diastolic pressor responses to angiotensin II infusions. At peak, 100 mg of losartan potassium inhibits these responses by approximately 85%; 24 hours after single and multiple-dose administration, inhibition is about 26-39%.
During losartan administration, removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity. Increases in plasma renin activity lead to increases in angiotensin II in plasma. During chronic (6 weeks) treatment of hypertensive patients with 100 mg/day losartan, approximately 2-3 fold increases of plasma angiotensin II were observed at time of peak plasma drug concentrations. In some patients, greater increases were observed, particularly during short term (2 weeks) treatment. However, antihypertensive activity and suppression of plasma aldosterone concentration were apparent at 2 and 6 weeks, indicating effective angiotensin II receptor blockade. After discontinuation of losartan, plasma renin activity and angiotensin II levels declined to untreated levels within 3 days.
Since losartan is a specific antagonist of the angiotensin II receptor type AT1, it does not inhibit ACE (kininase II), the enzyme that degrades bradykinin. In a study which compared the effects of 20 mg and 100 mg of losartan potassium and an ACE inhibitor on responses to angiotensin I, angiotensin II and bradykinin, losartan was shown to block responses to angiotensin I and angiotensin II without affecting responses to bradykinin. This finding is consistent with losartan's specific mechanism of action. In contrast, the ACE inhibitor was shown to block responses to angiotensin I and enhance responses to bradykinin without altering the response to angiotensin II, thus providing a pharmacodynamic distinction between losartan and ACE inhibitors.
Plasma concentrations of losartan and its active metabolite and the antihypertensive effect of losartan increase with increasing dose. Since losartan and its active metabolite are both angiotensin II receptor antagonists, they both contribute to the antihypertensive effect.
In a single-dose study in normal males, the administration of 100 mg of losartan potassium, under dietary high- and low-salt conditions, did not alter glomerular filtration rate, effective renal plasma flow or filtration fraction. Losartan had a natriuretic effect which was more pronounced on a low-salt diet and did not appear to be related to inhibition of early proximal reabsorption of sodium. Losartan also caused a transient increase in urinary uric acid excretion.
In nondiabetic hypertensive patients with proteinuria (≥2 g/24 hours) treated for 8 weeks, the administration of losartan potassium 50 mg titrated to 100 mg significantly reduced proteinuria by 42%. Fractional excretion of albumin and IgG also was significantly reduced. In these patients, losartan maintained glomerular filtration rate and reduced filtration fraction.
In postmenopausal hypertensive women treated for 4 weeks, 50 mg of losartan potassium had no effect on renal or systemic prostaglandin levels.
Losartan has no effect on autonomic reflexes and no sustained effect on plasma norepinephrine.
Losartan potassium, administered in doses of up to 150 mg once daily, did not cause clinically important changes in fasting triglycerides, total cholesterol or HDL-cholesterol in patients with hypertension. The same doses of losartan had no effect on fasting glucose levels.
Generally losartan caused a decrease in serum uric acid (usually <0.4 mg/dL) which was persistent in chronic therapy. In controlled clinical trials in hypertensive patients, no patients were discontinued due to increases in serum creatinine or serum potassium.
In a 12-week, parallel-design study in patients with left ventricular failure (New York Heart Association Functional Classes II-IV), most of whom were receiving diuretics and/or digitalis, losartan potassium administered in once-daily doses of 2.5, 10, 25 and 50 mg was compared to placebo. The 25-mg and 50-mg doses produced positive hemodynamic and neurohormonal effects which were maintained for the length of the study. Hemodynamic responses were characterized by an increase in cardiac index and decreases in: pulmonary capillary wedge pressure, systemic vascular resistance, mean systemic arterial pressure and heart rate. The occurrence of hypotension was dose related in these heart failure patients. Neurohormonal results were characterized by a reduction in circulating levels of aldosterone and norepinephrine.
Amlodipine: Hemodynamics: 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 oral 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 pressures (+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.
Electrophysiologic 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 on 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.
Pharmacokinetics: Absorption: Losartan: Following oral administration, losartan is well absorbed and undergoes first-pass metabolism, forming an active carboxylic acid metabolite and other inactive metabolites. The systemic bioavailability of losartan tablets is approximately 33%. Mean peak concentrations of losartan and its active metabolite are reached in 1 hour and in 3-4 hours, respectively. There was no clinically significant effect on the plasma concentration profile of losartan when the drug was administered with a standardized meal.
Amlodipine: After oral administration of therapeutic doses of amlodipine, absorption produces peak plasma concentrations between 6 and 12 hours. Absolute bioavailability has been estimated to be between 64 and 90%. The bioavailability of amlodipine is not altered by the presence of food.
Distribution: Losartan: Both losartan and its active metabolite are ≥99% bound to plasma proteins, primarily albumin. The volume of distribution of losartan is 34 liters. Studies in rats indicate that losartan crosses the blood-brain barrier poorly, if at all.
Amlodipine: Ex vivo studies have shown that approximately 93% of the circulating drug is bound to plasma proteins in hypertensive patients.
Metabolism: Losartan: About 14% of an intravenously- or orally-administered dose of losartan is converted to its active metabolite. Following oral and intravenous administration of 14C-labeled losartan potassium, circulating plasma radioactivity primarily is attributed to losartan and its active metabolite. Minimal conversion of losartan to its active metabolite was seen in about one percent of individuals studied.
In addition to the active metabolite, inactive metabolites are formed, including two major metabolites formed by hydroxylation of the butyl side chain and a minor metabolite, an N-2 tetrazole glucuronide.
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.
Elimination: Losartan: Plasma clearance of losartan and its active metabolite is about 600 mL/min and 50 mL/min, respectively. Renal clearance of losartan and its active metabolite is about 74 mL/min and 26 mL/min, respectively. When losartan is administered orally, about 4% of the dose is excreted unchanged in the urine, and about 6% of the dose is excreted in the urine as active metabolite. The pharmacokinetics of losartan and its active metabolite are linear with oral losartan potassium doses up to 200 mg.
Following oral administration, plasma concentrations of losartan and its active metabolite decline polyexponentially with a terminal half-life of about 2 hours and 6-9 hours, respectively. During once-daily dosing with 100 mg, neither losartan nor its active metabolite accumulates significantly in plasma.
Both biliary and urinary excretion contribute to the elimination of losartan and its metabolites. Following an oral dose of 14C-labeled losartan in man, about 35% of radioactivity is recovered in the urine and 58% in the feces. Following an intravenous dose of 14C-labeled losartan in man, about 43% of radioactivity is recovered in the urine and 50% in the feces.
Amlodipine: Elimination from the plasma is biphasic with a terminal elimination half-life of about 30-50 hours. Steady-state plasma levels of amlodipine are reached after 7 to 8 days of consecutive daily dosing.
Characteristics in Patients: LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ): LOSARTAN POTASSIUM + AMLODIPINE CAMSYLATE (COZAAR XQ) has not been studied in any special populations, due to the well known nature of losartan and amlodipine. Caution is advised for losartan in renal and hepatic impairment, and is contraindicated in breast feeding. No formal studies have been performed in either the elderly or children. For amlodipine caution is advised in hepatic impairment, and amlodipine is contraindicated in unstable cardiovascular disease and pregnancy/lactation.
Losartan: The plasma concentrations of losartan and its active metabolite observed in elderly male hypertensives are not significantly different from those observed in young male hypertensives.
Plasma concentrations of losartan were up to 2-fold higher in female hypertensives as compared to male hypertensives. Concentrations of the active metabolite were not different in males and females. This apparent pharmacokinetic difference is not judged to be of clinical significance.
Following oral administration in patients with mild to moderate alcoholic cirrhosis of the liver, plasma concentrations of losartan and its active metabolite were, respectively, 5-fold and 1.7-fold greater than those seen in young male volunteers.
Plasma concentrations of losartan are not altered in patients with creatinine clearance above 10 mL/min. Compared to patients with normal renal function, the AUC for losartan is approximately 2-fold greater in hemodialysis patients. Plasma concentrations of the active metabolite are not altered in patients with renal impairment or in hemodialysis patients. Neither losartan nor the active metabolite can be removed by hemodialysis.
Amlodipine: The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. Patients with renal failure may therefore receive the usual initial dose.
Elderly patients and patients with hepatic insufficiency have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40-60%, and a lower initial dose may be required. A similar increase in AUC was observed in patients with moderate to severe heart failure.
Sixty-two hypertensive patients aged 6 to 17 years received doses of amlodipine between 1.25 mg and 20 mg. Weight-adjusted clearance and volume of distribution were similar to values in adults.
MedsGo Class
Angiotensin II Antagonists / Calcium Antagonists
Features
Brand
Cozaar XQ
Full Details
Dosage Strength
100mg / 5mg
Drug Ingredients
- Amlodipine
- Losartan Potassium
Drug Packaging
Film-Coated Tablet 1's
Generic Name
Losartan Potassium / Amlodipine Camsilate
Dosage Form
Film-Coated Tablet
Registration Number
DRP-5347
Drug Classification
Prescription Drug (RX)
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