Colixtan

Yellow, round, biconvex, film-coated tablets, plain on both sides.
Each film-coated tablet contains: Losartan Potassium USP 50 mg, Amlodipine Besilate USP 5 mg.

Angiotensin II Receptor Blocker (ARB)/Calcium Channel Blocker (Dihydropyridine Derivative).
Pharmacology: Pharmacodynamics: Fixed-dose combination of Losartan and Amlodipine 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 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%. 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. 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.
Generally, Losartan caused a decrease in serum uric acid (usually <0.4 mg/dL) which was persistent in chronic therapy.
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. 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).
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.
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.
Amlodipine: 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.
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.
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.

Fixed-dose combination of Losartan and Amlodipine is indicated for the treatment of essential hypertension in adult patients whose blood pressure is not adequately controlled on either monotherapy.

Posology and method of administration: The recommended dose of Losartan and Amlodipine is one tablet per day. It may be administered with or without food. It is recommended to take the tablets with water. It 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 and Amlodipine is 100 mg/5 mg. A patient whose blood pressure is not adequately controlled with Losartan alone or Amlodipine alone may be switched to combination therapy with Fixed-dose combination of Losartan and Amlodipine. Fixed-dose combination of Losartan and Amlodipine 50 mg/5 mg may be administered in patients whose blood pressure is not adequately controlled with Amlodipine 5 mg or Losartan 50 mg alone. A patient co-administered with Losartan and Amlodipine may be switched to Fixed-dose combination of Losartan and Amlodipine (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 Fixed-dose combination of Losartan and Amlodipine 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 Fixed-dose combination of Losartan and Amlodipine, this dose should be achieved with Losartan monotherapy.
Use in patients with hepatic impairment: A lower dose of losartan (i.e. 25 mg once daily) is required for patients with a history of hepatic impairment, administration of Fixed-dose combination of Losartan and Amlodipine is not recommended.
Use in the elderly: There was no age-related difference in the efficacy or safety profile of Losartan. 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 Fixed-dose combination of Losartan and Amlodipine, this dose should be achieved with Amlodipine monotherapy.
Use in patients ≤18 years of age: Since safety and efficacy of Fixed-dose combination of Losartan and Amlodipine in children ≤18 years of age has not been established, administration of Fixed-dose combination of Losartan and Amlodipine is not recommended.

There are no data available in regard to overdosage of Losartan and Amlodipine in humans. The overdose on each ingredient of Amlodipine and Losartan are described.
Losartan: Symptoms of intoxication: The most likely manifestation of overdosage would be hypotension and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation.
Treatment of intoxication: If symptomatic hypotension should occur, supportive treatment should be instituted. Measures are depending on the time of medicinal product intake and kind and severity of symptoms. Stabilisation of the cardiovascular system should be given priority. After oral intake, the administration of a sufficient dose of activated charcoal is indicated. Afterwards, close monitoring of the vital parameters should be performed. Vital parameters should be corrected if necessary. Neither Losartan nor the active metabolite can be removed by hemodialysis.
Amlodipine: In humans, experience with intentional overdose is limited.
Symptoms: Available data suggest that gross overdosage could result in excessive peripheral vasodilatation and possibly reflex tachycardia. Marked and probably prolonged systemic hypotension up to and including shock with fatal outcome have been reported.
Treatment: Clinically significant hypotension due to Amlodipine overdosage calls for active cardiovascular support including frequent monitoring of cardiac and respiratory function, elevation of extremities and attention to circulating fluid volume and urine output. Frequent blood pressure measurements are essential.
If hypotension remains unresponsive to these conservative measures, consider administration of vasopressors (such as phenylephrine) with attention to circulating volume and urine output to restore vascular tone and blood pressure, provided that there is no contraindication to its use. Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade. Gastric lavage may be worthwhile in some cases. In healthy volunteers, the use of charcoal up to 2 hours after administration of Amlodipine 10 mg has been shown to reduce the absorption rate of Amlodipine. Since Amlodipine is highly protein-bound, dialysis is not likely to be of benefit.

Losartan and Amlodipine is contraindicated in patients who are hypersensitive to any component of this product Fixed-dose combination of Losartan and Amlodipine 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 and Amlodipine, or a lower starting dose should be used. Because of the gradual onset of action, acute hypotension is unlikely.
Liver function impairment: 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 (t_1/2) is 56 hours in patients with impaired hepatic function, titrate slowly when administering Amlodipine to patients with severe hepatic impairment.
Losartan: Fetal Toxicity: Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Fixed-dose combination of Losartan and 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. Concomitant use of other drugs that may increase serum potassium may lead 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 Patients with Heart Failure: Amlodipine was associated with increased reports of pulmonary edema despite no significant difference in the incidence of worsening heart failure as compared to placebo.
Effects on ability to drive and use machines: No studies of the effects of FDC of Losartan and Amlodipine on the ability to drive and operate machines have been performed. However, certain side effects that have been reported with FDC of Losartan and Amlodipine may affect some patients' ability to drive or operate machinery. Individual responses to FDC of Losartan and Amlodipine may vary.

Pregnancy: Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. When pregnancy is detected, discontinue Fixed-dose combination of Losartan and Amlodipine as soon as possible. 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 and Amlodipine as soon as possible. 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.
Breastfeeding: 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.

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).
Nervous system disorders: Common: Dizziness, headache.
Uncommon: Somnolence.
General disorders and administration site conditions: Uncommon: Asthenia, chest discomfort, chest pain, early satiety, edema peripheral, pitting edema.
Gastrointestinal disorders: Uncommon: Abdominal discomfort, dyspepsia, nausea, reflux esophagitis.
Skin and subcutaneous disorders: Uncommon: Pruritus (generalized), urticaria (generalized).
Cardiac disorder: Uncommon: Palpitation.
Vascular disorders: Uncommon: Flushing, orthostatic hypotension.
Respiratory, thoracic and mediastinal disorders: Uncommon: Dyspnea.
Sensory organ disorders: Uncommon: Vertigo.
Renal and urinary disorder: Uncommon: Pollakiuria.

Interaction with other medicinal products and other forms of interaction. No drug interaction studies have been conducted with Fixed-dose combination of Losartan and Amlodipine 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.
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. 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. Closely monitor blood pressure, renal function, and electrolytes in patients on Fixed-dose combination of Losartan and Amlodipine and other agents that affect the RAAS. Do not co-administer aliskiren with Losartan and Amlodipine in patients with diabetes. Avoid use of aliskiren with Fixed-dose combination of Losartan and Amlodipine in patients with renal impairment (GFR <60 mL/min).
Amlodipine: 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 coadministered with CYP3A4 inhibitors.
CYP3A4 Inducers: Patients should be monitored for adequate clinical effect when Amlodipine is co-administered with CYP3A4 inducers.

Instructions and special precautions for handling and disposal: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Store at temperatures not exceeding 30°C. Protect from light and moisture.

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.

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