Tozam 100/5/Tozam 100/10

Tozam 100/5: Orange colour, round shaped, biconvex. film-coated having break line on one side and plain on other side.
Each film-coated tablet contains: Losartan potassium 100mg, Amlodipine besilate Eq. to Amlodipine 5 mg.
Tozam 100/10: Red colour, round shaped, biconvex, film-coaled tablet having breakline on one side and plain on other side.
Each film-coated tablet contains: Losartan potassium 100mg, Amlodipine besilate Eq. to Amlodipine 10 mg.

Angiotensin II Receptor Blockers (ARB)/Calcium Channel Blocker.
Pharmacology: Pharmacodynamics: Losartan potassium + Amlodipine besilate 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 led 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.
Amlodipine: Hemodynamics: Following administration of therapeutic doses to patients with hypertension, amlodipine produces vasodilation resulting in 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.

Losartan potassium + Amlodipine besilate is indicated for the treatment of essential hypertension.
Losartan potassium + Amlodipine besilate may be used in patients whose blood pressure is not adequately controlled on either monotherapy.

The recommended dose of Losartan potassium + Amlodipine besilate is one tablet per day.
Losartan potassium + Amlodipine besilate may be administered with or without food. It is recommended to take Losartan potassium + Amlodipine besilate with water.
Losartan potassium + Amlodipine besilate 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 besilate 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 besilate.
Losartan potassium + Amlodipine besilate 5 mg/100 mg may be administered in patients whose blood pressure is not adequately controlled with amlodipine 5 mg or losartan 100 mg alone.
Losartan potassium + Amlodipine besilate 10 mg/100 mg may be administered in patients whose blood pressure is not adequately controlled with losartan 100 mg or Losartan Potassium + Amlodipine.
A patient co-administered with losartan and amlodipine may be switched to Losartan potassium + Amlodipine besilate (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 besilate 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. Since a 25 mg dose of losartan is not available with Losartan potassium + Amlodipine besilate, this dose should be achieved with losartan monotherapy.
Use in patients with hepatic impairment: In cases where a lower dose of losartan (ie., 25 mg once daily) is required for patients with a history of hepatic impairment, administration of Losartan Potassium + Amlodipine 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 besilate, this dose should be achieved with amlodipine monotherapy.
Use in patients ≤18 years of age: Since safety and efficacy of Losartan Potassium + Amlodipine in children ≤18 years of age has not been established, administration of Losartan Potassium + Amlodipine is not recommended.
Route of Administration: For oral administration only.

There are no data available in regard to overdosage of Losartan potassium + Amlodipine besilate 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 besilate equivalent to 40 mg amlodipine/kg and 100 mg amlodipine/kg in mice and rats, respectively, caused deaths. Single oral amlodipine besilate 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 potassium + Amlodipine besilate is contraindicated in patients who are hypersensitive to any component of this product. Losartan potassium + Amlodipine besilate should not be administered with aliskiren in patients with diabetes.

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, or a lower starting dose should be used. 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.
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 as soon as possible.
Hypersensitivity: Angioedema.
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.
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 besilate in children ≤18 years of age has not been established, administration Losartan Potassium + Amlodipine besilate is not recommended.
Neonates with a history of in utero exposure to Losartan Potassium + Amlodipine besilate: 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 the 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 besilate, this dose should be achieved with amlodipine monotherapy.

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 besilate as soon as possible.
Although there is no experience with the use of Losartan potassium + Amlodipine besilate 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 besilate 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 besilate 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 besilate, 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/hydrochlorothiazide for hypotension, oliguria, and hyperkalemia.
There are no adequate and well-controlled studies of amlodipine in pregnant women. The safety of amlodipine in pregnant women has not been established. Amlodipine has been shown to prolong both the gestation period and the duration of labor in rats at the dose 50 times the maximum recommended human dose.
Nursing mothers: While it is not known whether losartan or amlodipine is excreted in human milk, significant levels of amlodipine and/or losartan active metabolite were shown to be present in animal milk. Therefore, nursing mothers should not receive this drug.

The safety of Losartan potassium + Amlodipine besilate 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.)

Click on icon to see table/diagram/image

Additional information for each active ingredient: The following adverse reactions have been reported with the components of Losartan Potassium + Amlodipine.
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.)

Click on icon to see table/diagram/image

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.
The following additional adverse reactions have been reported in postmarketing 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-Schonlein 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 besilate: 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 besilate has been evaluated for safety in more than 11,000 patients in worldwide clinical trials. In general, treatment with amlodipine besilate was well-tolerated at doses up to 10 mg daily. Most adverse reactions reported during therapy with amlodipine besilate were of mild or moderate severity. In controlled clinical trials directly comparing amlodipine besilate (N=1730) at doses up to 10 mg to placebo (N=1250), discontinuation of amlodipine besilate 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.)

Click on icon to see table/diagram/image

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.)

Click on icon to see table/diagram/image

For several adverse experiences that appear to be drug and dose related, there was a greater incidence in women than men associated with amlodipine besilate treatment as shown in the following table: (See Table 5.)

Click on icon to see table/diagram/image

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.
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.
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.
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 post-marketing event has been reported infrequently where a causal relationship is uncertain: gynecomastia. In post-marketing 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 besilate.
Amlodipine besilate 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: 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 Losartan potassium + Amlodipine besilate. 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 Losartan potassium + Amlodipine besilate and 3.4% of patients treated with placebo developed hyperkalemia. 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.

No drug interaction studies have been conducted with Losartan potassium + Amlodipine besilate 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 and other agents that affect the RAAS. Do not co-administer aliskiren with Losartan Potassium + Amlodipine in patients with diabetes. Avoid use of aliskiren with Losartan Potassium + Amlodipine in patients with renal impairment (GFR<60 mL/min).
Grapefruit juice contains components that inhibit CYP 450 enzymes and may lower the concentration of the active metabolite of losartan which may reduce the therapeutic effect. Consumption of grapefruit juice should be avoided while taking Losartan Potassium + Amlodipine.
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.
СҮРЗА4 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.

Store at temperatures not exceeding 30°C.

Angiotensin II Antagonists / Calcium Antagonists

C09DB06 - losartan and amlodipine ; Belongs to the class of angiotensin II receptor blockers (ARBs) and calcium channel blockers. Used in the treatment of cardiovascular disease.

Rx