Lozap^® AM (Tablets) Instructions for Use

Marketing Authorization Holder

Sanofi Russia JSC (Russia)

ATC Code

C09DB06 (Losartan and Amlodipine)

Active Substances

Losartan (Rec.INN registered by WHO)

Amlodipine (Rec.INN registered by WHO)

Dosage Forms

	Lozap® AM	Film-coated tablets, 5 mg+50 mg: 10, 30, 100 or 300 pcs.
		Film-coated tablets, 5 mg+100 mg: 10, 30, 100 or 300 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white or almost white, oblong, biconvex, with an engraving “AT1” on one side.

Excipients: butylhydroxytoluene – 0.1 mg, sodium carboxymethyl starch – 17 mg, microcrystalline cellulose – 265.1 mg, mannitol – 40 mg, povidone K30 – 5 mg, crospovidone – 12 mg, magnesium stearate – 3 mg.

Shell composition hypromellose 2910 – 8 mg, hyprolose – 2 mg, titanium dioxide – 1.8 mg, talc – 0.2 mg.

10 pcs. – blisters (1) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (10) – cardboard packs.
30 pcs. – bottles (1) – cardboard packs.
100 pcs. – bottles (1) – cardboard packs.
300 pcs. – bottles (1) – cardboard packs.

Film-coated tablets pink or light pink, oblong, biconvex, with an engraving “AT2” on one side.

Excipients: butylhydroxytoluene – 0.1 mg, sodium carboxymethyl starch – 17 mg, microcrystalline cellulose – 407.1 mg, mannitol – 40 mg, povidone K30 – 5 mg, crospovidone – 18 mg, magnesium stearate – 5 mg.

Shell composition hypromellose 2910 – 12 mg, hyprolose – 3 mg, titanium dioxide – 2.7 mg, talc – 0.3 mg, iron oxide yellow dye – 0.045 mg, iron oxide red dye – 0.045 mg.

10 pcs. – blisters (1) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (10) – cardboard packs.
30 pcs. – bottles (1) – cardboard packs.
100 pcs. – bottles (1) – cardboard packs.
300 pcs. – bottles (1) – cardboard packs.

Clinical-Pharmacological Group

Combined antihypertensive drug (slow calcium channel blocker + angiotensin II receptor antagonist)

Pharmacotherapeutic Group

Combined antihypertensive agent (slow calcium channel blocker + angiotensin II receptor antagonist)

Pharmacological Action

The drug Lozap^® AM

Results from two bioequivalence studies in healthy volunteers showed that Lozap^® AM at doses of 5 mg+50 mg and 5 mg+100 mg is bioequivalent to the combined use of corresponding doses of amlodipine camsylate and losartan potassium as separate tablets.

Amlodipine

The bioequivalence of amlodipine besylate and amlodipine camsylate was evaluated in a randomized, blind, crossover comparative study in healthy volunteers. The results obtained in the study showed that 5 mg amlodipine camsylate tablets are bioequivalent to 5 mg amlodipine besylate tablets.

Mechanism of action

The drug Lozap^® AM

The drug contains two active substances with complementary mechanisms of action to improve BP control in patients with arterial hypertension: losartan potassium, an angiotensin II receptor antagonist (ARA II), and amlodipine, a slow calcium channel blocker (CCB). Losartan blocks the vasoconstrictive action of angiotensin II and its stimulation of aldosterone release by selectively inhibiting the binding of angiotensin II to AT₁ receptors in many tissues. Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle, leading to a reduction in peripheral vascular resistance and a decrease in BP.

Losartan

Angiotensin II is a potent vasoconstrictor, the primary active hormone of the RAAS, and a crucial pathophysiological link in the development of arterial hypertension. Angiotensin II binds to AT₁ receptors located in many tissues (vascular smooth muscle, adrenal glands, kidneys, and heart) and performs several important biological functions, including vasoconstriction and aldosterone release. Furthermore, angiotensin II stimulates the proliferation of smooth muscle cells. AT₂ receptors are a second type of receptor to which angiotensin II binds, but their role in regulating cardiovascular function is unknown.

Losartan is a selective, orally active antagonist of angiotensin II AT₁ receptors. Losartan and its pharmacologically active carboxylated metabolite (E-3174) block all physiological effects of angiotensin II in vitro and in vivo, regardless of its source or synthesis pathway. Unlike some peptide angiotensin II antagonists, losartan has no agonist properties.

Losartan selectively binds to AT₁ receptors and does not bind to or block receptors for other hormones and ion channels that play an important role in regulating cardiovascular function. Furthermore, Losartan does not inhibit ACE (kininase II), which is responsible for the degradation of bradykinin. Consequently, effects not directly related to AT₁ receptor blockade, such as enhancement of bradykinin-mediated effects or the development of edema (Losartan 1.7%, placebo 1.9%), are not relevant to the action of losartan.

Amlodipine

Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow channel blocker) that inhibits the transmembrane influx of calcium ions into vascular smooth muscle cells and cardiomyocytes. Experimental data suggest that Amlodipine binds to both dihydropyridine and non-dihydropyridine binding sites on slow calcium channel receptors. The process of myocardial and vascular smooth muscle contraction depends on the transmembrane influx of extracellular calcium ions through specific ion channels. Amlodipine selectively inhibits the transmembrane influx of calcium, exerting a greater effect on vascular smooth muscle cells than on cardiomyocytes.

A negative inotropic effect can be detected in vitro, but this effect has not been observed in studies in intact animals using therapeutic doses of amlodipine. Amlodipine does not affect serum calcium concentrations. Within the physiological pH range, Amlodipine is an ionized compound (pKa=8.6), and its kinetic interaction with the calcium channel receptor is characterized by a gradual association and dissociation with the receptor binding site, leading to a gradual onset of effect.

Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle, leading to a reduction in peripheral vascular resistance and a decrease in BP.

Pharmacodynamics

The drug Lozap^® AM

The drug has been shown to effectively reduce BP. Both Losartan and Amlodipine reduce BP by decreasing peripheral resistance. Blocking calcium entry into the cell and reducing the vasoconstrictive effect mediated by angiotensin II are complementary mechanisms.

Losartan

Losartan inhibits the increase in systolic and diastolic BP induced by angiotensin II infusion. At the time of reaching C_max of losartan in plasma after a 100 mg dose of losartan, the aforementioned effect of angiotensin II is suppressed by approximately 85%, and 24 hours after single and multiple doses, by 26-39%.

During losartan administration, the removal of the negative feedback loop involving angiotensin II suppression of renin secretion leads to an increase in plasma renin activity (PRA). The increase in PRA leads to an increase in plasma angiotensin II concentration. During long-term (6-week) treatment of patients with arterial hypertension with losartan 100 mg/day, a 2- to 3-fold increase in plasma angiotensin II concentration was observed at the time of C_max of losartan. In some patients, an even greater increase in angiotensin II concentration was observed, especially early in treatment (2 weeks). Despite this, the antihypertensive effect and the reduction in plasma aldosterone concentration were evident at 2 and 6 weeks of therapy, indicating effective blockade of angiotensin II receptors. After discontinuation of losartan, PRA and angiotensin II concentration decreased within 3 days to values observed before starting losartan.

Since Losartan is a specific antagonist of angiotensin II AT₁ receptors, it does not inhibit ACE (kininase II) – the enzyme that inactivates bradykinin. A study comparing the effects of losartan at doses of 20 mg and 100 mg with the effects of an ACE inhibitor on the responses to angiotensin I, angiotensin II, and bradykinin showed that Losartan blocked the effects of angiotensin I and angiotensin II without affecting the responses to bradykinin. This is due to the specific mechanism of action of losartan. The ACE inhibitor blocked the responses to angiotensin I and increased the severity of effects mediated by bradykinin, without affecting the response to angiotensin II, demonstrating a pharmacodynamic difference between losartan and ACE inhibitors.

The plasma concentrations of losartan and its active metabolite, as well as the hypotensive effect of losartan, increase with increasing dose of the drug. Since Losartan and its active metabolite are angiotensin II receptor antagonists, both contribute to the antihypertensive effect.

In a single-dose study of losartan 100 mg involving healthy (male) volunteers, oral administration under high- and low-salt diet conditions did not affect GFR, effective renal plasma flow, or filtration fraction. Losartan had a natriuretic effect, which was more pronounced on a low-salt diet and apparently not associated with suppression of early sodium reabsorption in the proximal renal tubules. Losartan also caused a transient increase in urinary uric acid excretion.

In patients with arterial hypertension, proteinuria (at least 2 g/24 h), without diabetes mellitus, taking Losartan for 8 weeks at a dose of 50 mg with a gradual increase to 100 mg, a significant reduction in proteinuria (by 42%), fractional excretion of albumin and immunoglobulins (IgG) was observed. In these patients, Losartan stabilized GFR and reduced the filtration fraction.

In postmenopausal women with arterial hypertension taking Losartan 50 mg for 4 weeks, no effect of therapy on renal and systemic prostaglandin levels was detected.

Losartan does not affect autonomic reflexes and does not have a long-term effect on plasma norepinephrine concentration.

In patients with arterial hypertension, Losartan at doses up to 150 mg/day did not cause clinically significant changes in fasting triglycerides, total cholesterol, and HDL cholesterol. At the same doses, Losartan had no effect on fasting blood glucose concentration.

Overall, Losartan caused a decrease in serum uric acid concentration (generally less than 0.4 mg/dl), which persisted during long-term treatment. In controlled clinical trials in patients with arterial hypertension, no drug discontinuations due to increased serum creatinine or potassium levels were reported.

In a 12-week parallel study involving patients with left ventricular failure (NYHA functional class II-IV), most of whom were taking diuretics and/or cardiac glycosides, the effects of losartan at doses of 2.5, 10, 25, and 50 mg/day were compared with placebo. At doses of 25 and 50 mg/day, the drug exhibited positive hemodynamic and neurohormonal effects that persisted throughout the study. Hemodynamic effects included an increase in cardiac index and a decrease in pulmonary capillary wedge pressure, as well as a reduction in systemic vascular resistance, mean systemic BP, and heart rate. The incidence of arterial hypotension in these patients was dose-dependent. Neurohormonal effects included a decrease in plasma aldosterone and norepinephrine concentrations.

Amlodipine

Hemodynamics. In patients with hypertension, administration of therapeutic doses of Amlodipine causes vasodilation, leading to a reduction in BP in the supine and standing positions. This reduction in BP is not accompanied by significant changes in heart rate or plasma catecholamine concentrations during long-term administration. Although hemodynamic studies in patients with stable exertional angina with single intravenous administration of amlodipine showed a decrease in BP and an increase in heart rate, in clinical studies, multiple oral administration of amlodipine did not lead to clinically significant changes in heart rate or BP in normotensive patients with exertional angina.

With long-term oral administration once daily, the antihypertensive effect persists for at least 24 hours. Plasma concentrations of amlodipine correlate with the antihypertensive effect in both young and elderly patients. The magnitude of the BP reduction with amlodipine also correlates with the severity of the BP elevation prior to treatment. Thus, in patients with moderate hypertension (diastolic pressure 105-114 mm Hg), the antihypertensive effect was approximately 50% greater than in patients with mild hypertension (diastolic pressure 90-104 mm Hg). In patients with normal BP, no clinically significant change in BP (+1/-2 mm Hg) was observed.

In patients with arterial hypertension and normal renal function, administration of therapeutic doses of amlodipine led to a reduction in renal vascular resistance, an increase in GFR and effective renal plasma flow without changes in filtration fraction or proteinuria.

As with other CCBs, hemodynamic parameters of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function taking Amlodipine generally showed a small increase in cardiac index without significant changes in the rate of left ventricular pressure rise at the beginning of ejection (dP/dt) or left ventricular end-diastolic pressure or volume. In hemodynamic studies, Amlodipine did not have a negative inotropic effect when used in therapeutic doses in healthy volunteers, even when used concomitantly with beta-blockers. However, similar results have been observed in healthy volunteers or in patients with compensated heart failure with drugs that have a pronounced negative inotropic effect.

Electrophysiological effects. Amlodipine did not affect sinoatrial node function or AV conduction in healthy volunteers. In patients with chronic stable angina, intravenous administration of 10 mg amlodipine did not significantly affect A-H and H-V conduction and sinus node recovery time after pacing. Similar results were obtained in patients taking Amlodipine and beta-blockers concomitantly. In clinical studies where patients with hypertension or angina took Amlodipine concomitantly with beta-blockers, no adverse effects on electrocardiographic parameters were observed. In clinical studies involving patients with angina only, amlodipine therapy did not affect electrocardiographic intervals and did not cause AV block to a greater extent.

Pharmacokinetics

Losartan

Absorption

When administered orally, Losartan is well absorbed and undergoes first-pass metabolism in the liver to form an active carboxylated metabolite and inactive metabolites. The systemic bioavailability of losartan in tablet form is about 33%. Mean C_max of losartan and its active metabolite are reached at 1 h and 3-4 h, respectively. When losartan was taken with a standard meal, no clinically significant effect on the plasma concentration profile of losartan was identified.

Distribution

Losartan and its active metabolite are at least 99% bound to plasma proteins (primarily albumin). The V_d of losartan is 34 L. Studies in rats have shown that Losartan practically does not cross the BBB.

With a dosing regimen of 100 mg once daily, no significant accumulation in plasma occurs for either losartan or its active metabolite. Losartan and its active metabolite exhibit linear pharmacokinetics with oral administration of losartan in doses up to 200 mg.

Metabolism

Approximately 14% of a losartan dose administered intravenously or orally is converted to its active metabolite. After oral administration or intravenous injection of carbon-14 labeled losartan (¹⁴C Losartan), the radioactivity in circulating plasma is primarily due to the presence of losartan and its active metabolite. Low efficiency of conversion of losartan to its active metabolite was observed in about 1% of patients in the study. In addition to the active metabolite, biologically inactive metabolites are formed, including two main ones formed by hydroxylation of the side butyl chain and one minor one, the N-2-tetrazole-glucuronide.

Excretion

The plasma clearance of losartan and its active metabolite is about 600 ml/min and 50 ml/min, respectively. The renal clearance of losartan and its active metabolite is approximately 74 ml/min and 26 ml/min, respectively. When losartan is taken orally, about 4% of the dose is excreted unchanged in the urine and about 6% of the dose is excreted in the urine as the active metabolite.

After oral administration, plasma concentrations of losartan and its active metabolite decline polyexponentially with a terminal T_1/2 of about 2 h and 6-9 h, respectively.

Elimination of losartan and its metabolites occurs via the kidneys and through the intestine with bile. After oral administration of ¹⁴C losartan in men, about 35% of radioactivity is found in the urine and 58% in the feces. After intravenous administration of ¹⁴C losartan in men, approximately 43% of radioactivity is found in the urine and 50% in the feces.

Pharmacokinetics in special clinical situations

Plasma concentrations of losartan and its active metabolite in elderly male patients with arterial hypertension do not differ significantly from these parameters in young male patients with arterial hypertension.

The plasma concentrations of losartan in women with arterial hypertension were twice as high as the corresponding values in men with arterial hypertension. The concentrations of the active metabolite did not differ between men and women. This apparent pharmacokinetic difference, however, is not clinically significant.

Following oral administration of losartan to patients with mild to moderate alcoholic liver cirrhosis, the plasma concentrations of losartan and its active metabolite were 5 and 1.7 times higher, respectively, than in young healthy male volunteers.

Plasma concentrations of losartan in patients with a creatinine clearance above 10 ml/min did not differ from those in patients with normal renal function. The AUC value of losartan in patients undergoing hemodialysis was approximately twice as high as the AUC value of losartan in patients with normal renal function. Plasma concentrations of the active metabolite were not altered in patients with impaired renal function or patients undergoing hemodialysis. Losartan and its active metabolite are not removed by the hemodialysis procedure.

Amlodipine

Absorption

Following oral administration at therapeutic doses, the C_max of amlodipine in plasma is reached within 6-12 hours. The absolute bioavailability of amlodipine ranges from 64% to 90% of the administered dose. Food intake does not affect the bioavailability of amlodipine.

Distribution

Studies have shown that in patients with arterial hypertension, approximately 93% of the circulating drug is bound to plasma proteins.

The C_ss of amlodipine in plasma is reached after 7-8 days of daily administration.

Metabolism and Excretion

Amlodipine is extensively (about 90%) metabolized in the liver to inactive metabolites. 10% of the administered dose is excreted by the kidneys as unchanged amlodipine and 60% as metabolites.

The elimination of amlodipine from plasma occurs in two phases, with a terminal phase T_1/2 of about 30-50 hours.

Pharmacokinetics in Special Clinical Cases

Renal impairment does not significantly affect the pharmacokinetic parameters of amlodipine; therefore, the usual initial dose of amlodipine can be prescribed to patients with renal failure.

In elderly patients and patients with hepatic impairment, the clearance of amlodipine is reduced, leading to an increase in AUC of approximately 40-60%. These patients may require a lower initial dose of amlodipine. A similar increase in AUC was observed in patients with moderate or severe heart failure.

Pharmacokinetic studies involving patients with arterial hypertension aged 6 to 17 years who took Amlodipine at doses ranging from 1.25 mg to 20 mg showed that the body weight-adjusted clearance and V_d of amlodipine were comparable to these parameters in adult patients.

Lozap^® AM

The drug has not been studied in any special patient groups due to the well-studied nature of its active substances, losartan and amlodipine. Losartan should be used with caution in patients with impaired renal or hepatic function. It is contraindicated during pregnancy and breastfeeding. No separate studies have been conducted in pediatric or elderly patients. Amlodipine should be used with caution in patients with impaired hepatic function. It is contraindicated in unstable cardiovascular disease, as well as during pregnancy and breastfeeding.

Indications

• Arterial hypertension (for patients who require combination therapy).

ICD codes

Dosage Regimen

Lozap^® AM is taken orally, regardless of meals, with a sufficient amount of water.

Lozap^® AM can be taken in combination with other antihypertensive agents. Patients who have not achieved adequate blood pressure control with losartan or amlodipine monotherapy may switch to combination therapy with Lozap^® AM.

The recommended dose is 1 tablet once daily.

The maximum recommended dose is 5 mg+100 mg once daily.

Lozap^® AM at a dose of 5 mg+50 mg is prescribed to patients who have not achieved adequate blood pressure control with amlodipine 5 mg or losartan 50 mg monotherapy.

Lozap^® AM at a dose of 5 mg+100 mg is prescribed to patients who have not achieved adequate blood pressure control with losartan 100 mg or Lozap^® AM at a dose of 5 mg+50 mg.

Patients receiving combination therapy with amlodipine and losartan as separate medicinal products may switch to the combined drug Lozap^® AM (a fixed-dose combination containing the same doses of amlodipine and losartan) to improve treatment adherence.

In patients with impaired renal function (creatinine clearance 20-50 ml/min), dose adjustment is not required. The use of the drug is not recommended for patients with moderate renal impairment. The use of Lozap^® AM is contraindicated in patients with severe renal impairment or patients undergoing hemodialysis.

If there is a therapeutic need to use Lozap^® AM in patients with reduced blood volume, patients with impaired hepatic function, or elderly patients, an individual selection of doses of the active substances (amlodipine and losartan) should be performed before starting the fixed-dose combination drug.

In patients with reduced blood volume (e.g., those receiving high-dose diuretic therapy), the recommended initial dose of losartan is 25 mg once daily. Since Lozap^® AM does not have a dosage containing Losartan 25 mg, losartan monotherapy should be prescribed.

The use of Lozap^® AM is not recommended in patients with a history of hepatic impairment who require low doses of losartan (i.e., 25 mg once daily). Recommended doses of amlodipine have not been studied in patients with mild to moderate hepatic impairment. The use of the drug is contraindicated in patients with severe hepatic impairment.

In elderly patients, due to reduced clearance, amlodipine therapy is usually recommended to start at a dose of 2.5 mg once daily. Since Lozap^® AM does not have a dosage containing Amlodipine 2.5 mg, amlodipine monotherapy should be prescribed.

Since the efficacy and safety of Lozap^® AM in patients under 18 years of age have not been studied, the use of the drug in this group of patients is contraindicated.

Adverse Reactions

Lozap^® AM

The safety of Lozap^® AM was evaluated in clinical studies over 8 weeks involving 646 patients with arterial hypertension, of which 325 patients received combination therapy with Amlodipine+Losartan. The following adverse events, assessed by investigators as possibly, probably, or definitely related to the drug, were observed during clinical studies (frequent ≥1% and <10%; infrequent ≥0.1% and <1%).

Nervous system disorders frequent – dizziness, headache; infrequent – drowsiness.

Gastrointestinal disorders infrequent – abdominal discomfort, dyspepsia, nausea, reflux esophagitis.

Skin and subcutaneous tissue disorders infrequent – skin itching (generalized), urticaria (generalized).

Cardiac disorders: infrequent – palpitations.

Vascular disorders infrequent – flushing, orthostatic hypotension.

Respiratory, thoracic and mediastinal disorders infrequent – dyspnea.

Ear and labyrinth disorders infrequent – vertigo.

Renal and urinary disorders infrequent – pollakiuria.

General disorders and administration site conditions infrequent – asthenia, chest discomfort, chest pain, feeling of rapid satiety, peripheral edema.

The following adverse events were observed with the use of the active substances included in Lozap^® AM as monotherapy.

Losartan

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of one drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In general, Losartan is well tolerated by patients with arterial hypertension. Adverse events are mild and transient and do not require discontinuation of therapy. The overall incidence of adverse events with losartan is comparable to that with placebo. In controlled clinical trials, the rate of therapy discontinuation due to clinically significant adverse events was 2.3% in the group of patients taking Losartan and 3.7% in the group of patients taking placebo. In controlled clinical trials of losartan in patients with arterial hypertension, the only treatment-related adverse reaction that occurred with an incidence greater than placebo was dizziness, which was observed in the losartan treatment groups with an incidence of 1% or more. In addition, dose-dependent orthostatic reactions were observed in less than 1% of patients. Rash was reported rarely (≥0.01% and <0.1% of cases), but its incidence was less than with placebo.

In double-blind controlled clinical studies, the following adverse events were observed in ≥1% of patients with arterial hypertension receiving losartan (n=2085) or placebo (n=535), regardless of their relationship to treatment.

General disorders and administration site conditions abdominal pain 1.7% (placebo 1.7%); asthenia and fatigue 3.8% (3.9%); chest pain 1.1% (2.6%); peripheral edema 1.7% (1.9%).

Cardiac disorders palpitations 1.0% (placebo 0.4%); tachycardia 1.0% (1.7%).

Gastrointestinal disorders diarrhea 1.9% (placebo 1.9%); dyspepsia 1.1% (1.5%); nausea 1.8% (2.8%).

Musculoskeletal and connective tissue disorders back pain 1.6% (placebo 1.1%); muscle cramps 1.0% (1.1%).

Nervous system disorders dizziness 4.1% (placebo 2.4%); headache 14.1% (17.2%); insomnia 1.1% (0.7%).

Respiratory, thoracic and mediastinal disorders cough 3.1% (placebo 2.6%); nasal congestion 1.3% (1.1%); pharyngitis 1.5% (2.6%); sinusitis 1.0% (1.3%); upper respiratory tract infection 6.5% (5.6%).

Controlled clinical trials have shown that Losartan is generally well tolerated by patients with arterial hypertension and left ventricular hypertrophy. The most frequent adverse reactions associated with losartan were systemic and non-systemic dizziness, asthenia/weakness.

In this study, in patients without a history of diabetes mellitus, the incidence of new-onset diabetes mellitus was lower with losartan compared to atenolol (p <0.001). Since there was no placebo group in this study, it is unknown whether this is a positive effect of losartan or an adverse effect of atenolol.

Controlled clinical trials have shown that Losartan is generally well tolerated by patients with type 2 diabetes mellitus and proteinuria. The most frequent adverse reactions associated with losartan were dizziness, asthenia/weakness, pronounced decrease in blood pressure, and hyperkalemia (see section “Special Instructions”).

The following adverse reactions have been observed in clinical practice during the post-marketing period.

Hypersensitivity reactions anaphylactic reactions, angioedema involving the larynx and glottis, causing airway obstruction, and/or angioedema of the face, lips, pharynx, and/or tongue have been rarely observed in patients taking Losartan. Some of these patients had a history of angioedema with other drugs, including ACE inhibitors. Vasculitis, including Henoch-Schönlein purpura, has been rarely reported.

Gastrointestinal disorders hepatitis (rare), impaired liver function, vomiting.

General disorders and administration site conditions malaise.

Blood and lymphatic system disorders anemia, thrombocytopenia (rare).

Musculoskeletal and connective tissue disorders myalgia, arthralgia.

Nervous system disorders migraine, dysgeusia.

Reproductive system and breast disorders erectile dysfunction/impotence.

Respiratory, thoracic and mediastinal disorders cough.

Skin and subcutaneous tissue disorders urticaria, pruritus, erythema, photosensitivity.

Amlodipine besylate

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of one drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of amlodipine besylate has been evaluated in clinical trials involving more than 11,000 patients. In general, treatment with amlodipine besylate at doses up to 10 mg once daily was well tolerated. Most of the adverse events observed during therapy with amlodipine besylate were mild or moderate in severity. In controlled clinical trials directly comparing therapy with amlodipine besylate at doses up to 10 mg once daily with placebo, discontinuation of amlodipine besylate therapy due to adverse events was required in only 1.5% of patients, which was not significantly different from the placebo group (about 1%). The most frequent (≥1% and <10%) adverse events are headache and edema.

The following frequency (%) of dose-dependent adverse events was observed

The following adverse events were frequently (≥0.1% and <1%) observed in patients in controlled clinical trials or in open-label studies or in the post-marketing period, where the causal relationship is unknown (listed to inform about a possible causal relationship)

Cardiac disorders arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, pronounced decrease in blood pressure, peripheral ischemia, syncope, tachycardia, postural dizziness, postural hypotension, vasculitis.

Nervous system disorders hypoesthesia, peripheral neuropathy, paresthesia, tremor, vertigo.

Autonomic nervous system disorders dry mouth, increased sweating.

Psychiatric disorders sexual dysfunction (in men* and women), insomnia, increased excitability, depression, abnormal dreams, anxiety, depersonalization.

Eye disorders visual impairment, conjunctivitis, diplopia, eye pain, tinnitus.

Respiratory, thoracic and mediastinal disorders dyspnea*, epistaxis.

Gastrointestinal disorders anorexia, constipation, dyspepsia*, dysphagia, diarrhea, flatulence, pancreatitis, vomiting, gingival hyperplasia.

Renal and urinary disorders micturition frequency, micturition disorder, nocturia.

Musculoskeletal and connective tissue disorders arthralgia, arthrosis, muscle cramps*, myalgia.

Skin and subcutaneous tissue disorders angioedema, erythema multiforme, pruritus*, skin rash*, erythematous rash, maculopapular rash.

Metabolism and nutrition disorders hyperglycemia, thirst.

Blood and lymphatic system disorders leukopenia, purpura, thrombocytopenia.

General disorders and administration site conditions allergic reaction, asthenia*, back pain, flushing, malaise, pain, rigors, weight increased, weight decreased.

*These adverse events were observed in less than 1% in placebo-controlled trials; but their frequency was from 1% to 2% in all multiple-dose studies of amlodipine.

The following adverse events were observed very rarely (<0.1%): heart failure, arrhythmia, extrasystoles, skin depigmentation, urticaria, skin dryness, alopecia, dermatitis, muscle weakness, muscle twitching, ataxia, increased blood pressure, migraine, cold and clammy skin, apathy, agitation, amnesia, gastritis, increased appetite, frequent loose stools, cough, rhinitis, dysuria, polyuria, parosmia, taste disturbance, accommodation disturbance, and xerophthalmia.

Other adverse events were observed sporadically, and it is impossible to establish a causal relationship with drug administration or concomitant diseases, such as myocardial infarction and angina.

The following adverse events have also been observed in the post-marketing surveillance period. Since these adverse 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. An adverse event that has been observed rarely in post-marketing surveillance without an established causal relationship: gynecomastia. In the post-marketing surveillance period, jaundice and elevated liver enzymes (mostly consistent with cholestasis or hepatitis), in some cases severe enough to require hospitalization, and toxic epidermal necrolysis (frequency cannot be estimated) have been observed with amlodipine besylate.

Amlodipine besylate has been safely used in patients with COPD, compensated chronic heart failure, coronary artery disease, peripheral vascular disease, diabetes mellitus, and abnormal lipid profile.

Laboratory Parameters

Lozap^® AM preparation

In some patients, after 8 weeks of simultaneous administration of amlodipine and losartan, a decrease in heart rate was observed, but it was not clinically significant.

In some patients, an increase in blood creatinine and an increase in liver enzyme activity were observed; however, specific laboratory monitoring is not required.

Losartan

In controlled clinical trials in patients with arterial hypertension, clinically significant changes in standard laboratory parameters were rarely associated with losartan administration. Hyperkalemia (serum potassium greater than 5.5 mEq/L) was observed in 1.5% of patients. In a clinical trial in patients with type 2 diabetes mellitus with proteinuria, hyperkalemia developed in 9.9% of patients taking Losartan and in 3.4% of patients taking placebo. Increased ALT activity was observed in rare cases and usually returned to normal after discontinuation of therapy.

Amlodipine

No clinically significant changes in standard laboratory parameters associated with amlodipine therapy were observed. No clinically significant changes in serum potassium, serum glucose, triglycerides, total cholesterol, HDL cholesterol, uric acid, blood urea nitrogen, or creatinine were observed.

Contraindications

• Hypersensitivity to the components of the drug;
• Severe hepatic impairment (more than 9 points on the Child-Pugh scale);
• Shock (including cardiogenic shock);
• Obstruction of the left ventricular outflow tract (e.g., severe aortic stenosis);
• Hemodynamically unstable heart failure after acute myocardial infarction;
• Use in patients with renal impairment (creatinine clearance less than 20 ml/min) or patients on hemodialysis;
• Severe arterial hypotension (systolic BP less than 90 mm Hg);
• Concomitant use with aliskiren or aliskiren-containing drugs in patients with diabetes mellitus and/or moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m² body surface area);
• Concomitant use with ACE inhibitors in patients with diabetic nephropathy;
• Pregnancy;
• Breastfeeding period;
• Age under 18 years (efficacy and safety of use have not been established).

With caution the drug should be prescribed for bilateral renal artery stenosis or stenosis of the artery of a single kidney; hyperkalemia; condition after kidney transplantation (no experience of use); aortic or mitral stenosis; hypertrophic obstructive cardiomyopathy; heart failure with concomitant severe renal impairment; severe heart failure (NYHA class III-IV); heart failure with life-threatening arrhythmias; coronary artery disease; cerebrovascular diseases; primary hyperaldosteronism; history of angioedema; hepatic impairment (less than 9 points on the Child-Pugh scale); unstable angina or myocardial infarction; sick sinus syndrome; arterial hypotension; concomitant use with inhibitors and inducers of the CYP3A4 isoenzyme; water-electrolyte imbalance; renal failure; patients with reduced blood volume (e.g., those receiving treatment with high doses of diuretics) – symptomatic arterial hypotension may occur.

Use in Pregnancy and Lactation

The use of Lozap^® AM is contraindicated during pregnancy and breastfeeding.

Pregnancy

Losartan

Drugs that act directly on the RAAS can cause serious damage and death to the developing fetus; therefore, if pregnancy is diagnosed, Lozap^® AM should be discontinued immediately and, if necessary, alternative antihypertensive therapy should be prescribed.

Although there is no experience with the use of Lozap^® AM in pregnant women, preclinical animal studies have shown that losartan administration leads to serious embryonic and neonatal damage and fetal or offspring death. The mechanism of these phenomena is believed to be due to the effect on the RAAS.

Fetal renal perfusion, which depends on the development of the RAAS, appears in the second trimester; therefore, the risk to the fetus increases if Lozap^® AM is used in the second or third trimester of pregnancy.

The use of drugs affecting the RAAS during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and mortality. The development of oligohydramnios may be associated with fetal lung hypoplasia and skeletal deformities. Possible adverse events in newborns include skull hypoplasia, anuria, arterial hypotension, renal failure, and death.

The adverse outcomes described above are usually associated with the use of drugs affecting the RAAS during the second and third trimesters of pregnancy. Most epidemiological studies on the development of fetal abnormalities after the use of antihypertensive drugs in the first trimester of pregnancy did not reveal differences between drugs affecting the RAAS and other antihypertensive drugs. When prescribing antihypertensive therapy to pregnant women, it is important to optimize possible outcomes for the mother and fetus.

If it is impossible to select alternative therapy instead of drugs affecting the RAAS, the patient should be informed about the potential risk of therapy to the fetus. Periodic ultrasound examinations should be performed to assess the intra-amniotic space. If oligohydramnios is detected, Lozap^® AM should be discontinued, unless it is considered life-saving for the mother. Depending on the week of pregnancy, appropriate fetal tests should be performed. Patients and physicians should be aware that oligohydramnios may not be detected until irreversible fetal damage has occurred. Careful monitoring of newborns whose mothers took Lozap^® AM during pregnancy is necessary to monitor for arterial hypotension, oliguria, and hyperkalemia.

Amlodipine

No adequate and controlled studies have been conducted on the use of amlodipine in pregnant women.

Breastfeeding period

Losartan

Due to the lack of sufficient safety information, the use of losartan during breastfeeding is contraindicated. Preference should be given to alternative treatment with an established safety profile, especially when nursing a newborn or premature infant.

Amlodipine

Amlodipine is excreted in breast milk in an amount of 3-7% of the maternal dose (up to 15% maximum). The effect of amlodipine on newborns is unknown.

A decision should be made whether to discontinue breastfeeding or to discontinue the drug, taking into account the importance of breastfeeding for the child and the continuation of therapy for the mother.

Fertility

Losartan

There are no clinical data on the effect of losartan on fertility.

Amlodipine

Reversible biochemical changes in the head of spermatozoa were observed in some patients taking CCBs. There is insufficient clinical data to assess the possible effect of amlodipine on fertility.

Use in Hepatic Impairment

Contraindicated in severe hepatic impairment (more than 9 points on the Child-Pugh scale).

With caution the drug should be prescribed for hepatic impairment (less than 9 points on the Child-Pugh scale).

Use in Renal Impairment

Contraindicated in patients with renal impairment (creatinine clearance less than 20 ml/min) or patients on hemodialysis.

With caution the drug should be prescribed for renal failure; bilateral renal artery stenosis or stenosis of the artery of a single kidney; condition after kidney transplantation (no experience of use).

Pediatric Use

The efficacy and safety of the drug in children and adolescents under 18 years of age have not been established; therefore, the use of the drug in this group of patients is contraindicated.

Geriatric Use

In elderly patients, due to reduced clearance, amlodipine therapy is usually recommended to be started at a dose of 2.5 mg once daily. Since Lozap^® AM does not have a dosage containing Amlodipine 2.5 mg, amlodipine monotherapy should be prescribed.

Special Precautions

Lozap^® AM preparation

Arterial hypotension

Symptomatic arterial hypotension may be observed in patients with reduced blood volume (e.g., those receiving treatment with high doses of diuretics) or with severe aortic stenosis. Correction of such conditions should be carried out before prescribing Lozap^® AM or treatment should be started with a lower dose of the drug. Acute arterial hypotension is unlikely due to the gradual onset of action of the drug.

Hepatic impairment

Based on pharmacokinetic data, which showed a significant increase in plasma concentrations of losartan in patients with liver cirrhosis, lower doses of losartan should be prescribed to patients with a history of hepatic impairment.

Since Amlodipine is mainly metabolized in the liver and T_1/2 in patients with hepatic impairment is 56 hours, when prescribing amlodipine to patients with severe hepatic impairment, dose titration should be carried out gradually.

Losartan

Hypersensitivity reactions

In patients with a history of angioedema (swelling of the face, lips, pharynx/larynx, and/or tongue), control of drug use is necessary.

Embryo-fetal toxicity

The use of drugs affecting the RAAS during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and mortality. The development of oligohydramnios may be associated with fetal lung hypoplasia and skeletal deformities. Possible adverse events in newborns include skull hypoplasia, anuria, arterial hypotension, renal failure, and death. If pregnancy is diagnosed, Lozap^® AM should be discontinued immediately.

Water-electrolyte imbalance

Water-electrolyte imbalance is characteristic of patients with renal impairment with or without diabetes mellitus; therefore, careful monitoring of these patients is necessary. In clinical trials involving patients with type 2 diabetes mellitus with proteinuria, the number of cases of hyperkalemia was greater in the group taking Losartan than in the group taking placebo. Several patients discontinued therapy due to hyperkalemia.

During losartan administration, patients should not take potassium preparations or potassium-containing salt substitutes without prior consultation with a physician.

Aortic or mitral stenosis, hypertrophic obstructive cardiomyopathy

Like all drugs with vasodilating action, ARBs should be prescribed with caution to patients with aortic or mitral stenosis or hypertrophic obstructive cardiomyopathy.

Coronary artery disease and cerebrovascular diseases

Like all drugs with vasodilating action, ARBs should be prescribed with caution to patients with coronary artery disease or cerebrovascular diseases, since an excessive decrease in BP in patients of this group may lead to the development of myocardial infarction or stroke.

Chronic heart failure (CHF)

As with the use of other drugs that affect the RAAS, in patients with CHF and with or without renal impairment, there is a risk of developing severe arterial hypotension or acute renal failure. Since there is insufficient experience with the use of losartan in patients with heart failure and concomitant severe renal impairment, in patients with severe heart failure (NYHA class III-IV), as well as in patients with heart failure and symptomatic life-threatening arrhythmias, Losartan should be prescribed with caution to patients in these groups.

In patients with chronic heart failure of non-ischemic origin NYHA class III-IV, an increase in the incidence of pulmonary edema was noted during amlodipine use, despite the absence of signs of worsening heart failure.

Primary hyperaldosteronism

Since patients with primary hyperaldosteronism usually do not respond positively to antihypertensive therapy that acts by inhibiting the RAAS, the use of losartan is not recommended in patients of this group.

Hepatic impairment

Pharmacokinetic data indicate that the plasma concentration of losartan in patients with liver cirrhosis is significantly increased; therefore, patients with a history of liver disease should be prescribed Losartan at a lower dose. There is no experience with the use of losartan in patients with severe hepatic impairment; therefore, the drug should not be used in patients of this group.

Renal impairment

Due to inhibition of the RAAS, changes in renal function, including the development of renal failure, have been observed in some predisposed patients. These changes may resolve after discontinuation of treatment.

Some drugs affecting the RAAS may increase blood urea and serum creatinine concentrations in patients with bilateral renal artery stenosis or stenosis of the renal artery of a single kidney. The occurrence of similar effects has been reported with losartan. Such renal function impairments may be reversible after discontinuation of therapy. Losartan should be used with caution in patients with bilateral renal artery stenosis or stenosis of the renal artery of a single kidney.

Hypertensive crisis

The efficacy and safety of Lozap^® AM in hypertensive crisis have not been established.

Amlodipine

Maintenance of dental hygiene and observation by a dentist are necessary (to prevent soreness, bleeding, and gingival hyperplasia).

Unstable angina and myocardial infarction

After initiation of therapy or an increase in the dose of amlodipine, unstable angina and acute myocardial infarction may develop, especially in patients with severe hypertrophic obstructive cardiomyopathy.

Use in pediatrics

The efficacy and safety of Lozap^® AM in children and adolescents under 18 years of age have not been established.

If newborns whose mothers took Lozap^® AM during pregnancy develop oliguria or arterial hypotension, symptomatic therapy aimed at maintaining BP and renal perfusion should be carried out. Blood transfusion or dialysis may be required to prevent the development of arterial hypotension and/or maintain renal function.

Elderly patients

Clinical trials did not reveal any specific safety or efficacy features of losartan in elderly patients (over 65 years). In elderly patients, due to reduced clearance, leading to an increase in the AUC of amlodipine by approximately 40-60%, amlodipine therapy is usually recommended to be started at a dose of 2.5 mg once daily. Since Lozap^® AM does not have a dosage containing Amlodipine 2.5 mg, amlodipine monotherapy should be prescribed.

Effect on the ability to drive vehicles and operate machinery

No studies have been conducted to assess the effect on the ability to drive vehicles and operate machinery; however, some adverse effects observed with the use of Lozap^® AM may affect the ability to drive vehicles and operate machinery.

Overdose

Lozap^® AM preparation

There are no data on drug overdose. Overdoses of amlodipine and losartan have been described.

Losartan

Symptoms information on overdose is limited. The most likely manifestation of overdose is a pronounced decrease in BP and tachycardia; bradycardia may occur due to parasympathetic (vagal) stimulation.

Treatment symptomatic therapy. Losartan and its active metabolite are not removed by hemodialysis.

Amlodipine

Symptoms overdose can lead to excessive peripheral vasodilation with a pronounced decrease in BP and possible development of reflex tachycardia. Pronounced and prolonged systemic hypotensive effect up to shock with fatal outcome has been reported.

Treatment gastric lavage is indicated if necessary. Administration of activated charcoal to healthy volunteers immediately within 2 hours after oral administration of 10 mg of amlodipine led to a decrease in its absorption. In case of significant amlodipine overdose, hemodynamic and respiratory parameters should be actively monitored. Frequent measurement of BP is necessary. If arterial hypotension occurs, hemodynamic support should be provided, including elevation of the limbs and adequate fluid administration. If arterial hypotension remains resistant to these conservative measures, the administration of vasoconstrictor drugs (e.g., phenylephrine) should be considered, taking into account blood volume and diuresis. Intravenous administration of calcium gluconate is effective to eliminate calcium channel blockade. Since Amlodipine is highly bound to plasma proteins, hemodialysis is not effective.

Drug Interactions

Lozap^® AM preparation

No studies on drug interactions of Lozap^® AM with other drugs have been conducted. Studies of drug interactions of the active substances included in the drug are described below.

Losartan

In clinical studies on pharmacokinetic drug interactions, no clinically significant interaction of losartan with hydrochlorothiazide, digoxin, warfarin, cimetidine, and phenobarbital was identified. Rifampicin, being an inducer of drug metabolism, reduces the blood concentration of the active metabolite of losartan. The use of two inhibitors of the cytochrome P450 3A4 isoenzyme: ketoconazole and erythromycin was studied in clinical trials. Ketoconazole did not affect the metabolism of losartan to the active metabolite after intravenous administration of losartan. Erythromycin did not have a clinically significant effect when losartan was taken orally. Fluconazole, an inhibitor of the cytochrome P450 2C9 isoenzyme, reduced the concentration of the active metabolite of losartan; however, the pharmacodynamic significance of the concomitant use of losartan and inhibitors of the cytochrome P450 2C9 isoenzyme has not been studied. It has been shown that in patients who do not metabolize Losartan to the active metabolite, there is a very rare and specific defect of the cytochrome P450 2C9 isoenzyme. These data suggest that the metabolism of losartan to the active metabolite is carried out by the cytochrome P450 2C9 isoenzyme, and not by the cytochrome P450 3A4 isoenzyme.

Concomitant use of losartan, like other drugs that block angiotensin II and its effects, with potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium-containing supplements, or potassium salts may lead to an increase in serum potassium.

As with the use of other drugs affecting lithium excretion, Losartan may decrease lithium excretion; therefore, when lithium preparations and ARBs are used concomitantly, serum lithium concentrations should be monitored carefully.

NSAIDs, including selective COX-2 inhibitors, may reduce the effects of diuretics and other antihypertensive drugs. Consequently, the antihypertensive effect of ARBs or ACE inhibitors may be attenuated when used concomitantly with NSAIDs, including selective COX-2 inhibitors.

In some patients with impaired renal function (e.g., elderly patients or patients with dehydration, including those taking diuretics) receiving therapy with NSAIDs, including selective COX-2 inhibitors, the concomitant use of ARBs or ACE inhibitors may cause further deterioration of renal function, including the development of acute renal failure. These effects are usually reversible, so the concomitant use of these drugs should be carried out with caution in patients with impaired renal function.

Dual blockade of the RAAS with ARBs, ACE inhibitors, or aliskiren (a renin inhibitor) is associated with an increased risk of arterial hypotension, syncope, hyperkalemia, and impaired renal function (including acute renal failure) compared to monotherapy. Regular monitoring of blood pressure, renal function, and blood electrolyte levels is necessary in patients taking Lozap^® AM concomitantly with other drugs affecting the RAAS.

The concomitant use of ARBs with drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or with moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m² body surface area) and is not recommended in other patients.

The concomitant use of ARBs with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Amlodipine

In vitro study data

In vitro study data have shown that Amlodipine does not affect the plasma protein binding of digoxin, phenytoin, warfarin, and indomethacin.

Cimetidine

Concomitant use of amlodipine and cimetidine does not affect the pharmacokinetics of amlodipine.

Grapefruit juice

Co-administration of 240 ml of grapefruit juice with a single oral 10 mg dose of amlodipine in healthy volunteers did not significantly affect the pharmacokinetics of amlodipine.

Antacids containing magnesium or aluminum hydroxide

Co-administration of an antacid containing magnesium or aluminum hydroxide with a single dose of amlodipine did not significantly affect the pharmacokinetics of amlodipine.

Sildenafil

A single 100 mg dose of sildenafil in patients with arterial hypertension did not affect the pharmacokinetics of amlodipine. When amlodipine was taken concomitantly with sildenafil, each drug independently exerted its antihypertensive effect.

Atorvastatin

Concomitant multiple administration of amlodipine 10 mg with atorvastatin 80 mg did not lead to significant changes in the steady-state pharmacokinetic parameters of atorvastatin.

Simvastatin

Concomitant multiple administration of amlodipine 10 mg with simvastatin 80 mg resulted in a 77% increase in simvastatin exposure compared to simvastatin monotherapy. The dose of simvastatin when used concomitantly with amlodipine should not exceed 20 mg once daily.

Tacrolimus

When used concomitantly with amlodipine, there is a risk of increased plasma concentrations of tacrolimus. To avoid tacrolimus toxicity during concomitant use with amlodipine, plasma tacrolimus concentrations should be monitored in patients and the tacrolimus dose should be adjusted if necessary.

Cyclosporine

In a prospective study in kidney transplant patients, the use of amlodipine resulted in an average 40% increase in the minimum blood concentration of cyclosporine. Concomitant use of amlodipine with cyclosporine may increase cyclosporine concentrations. The minimum concentration of cyclosporine should be monitored during concomitant use with Lozap^® AM, as it contains Amlodipine.

Dantrolene

With intravenous administration of dantrolene during amlodipine therapy, collapse, arrhythmia, decreased myocardial contractility, and hyperkalemia may occur.

Digoxin

Concomitant administration of amlodipine and digoxin did not change serum digoxin concentrations or renal clearance of digoxin in healthy volunteers.

Ethanol (alcohol)

Single and multiple administration of amlodipine 10 mg did not significantly affect the pharmacokinetics of ethanol.

Warfarin

Concomitant administration of amlodipine and warfarin does not affect the increase in prothrombin time in response to warfarin use.

Inhibitors of the CYP3A4 isoenzyme

In elderly patients with arterial hypertension, concomitant use of diltiazem at a daily dose of 180 mg and amlodipine 5 mg led to a 1.6-fold increase in the AUC of amlodipine. In healthy volunteers, concomitant use of erythromycin and amlodipine did not significantly affect the AUC of amlodipine, but in elderly patients, the change in amlodipine exposure may be more pronounced. Nevertheless, strong inhibitors of the CYP3A4 isoenzyme (e.g., ketoconazole, itraconazole, ritonavir) may increase plasma concentrations of amlodipine to a greater extent. When amlodipine and CYP3A4 isoenzyme inhibitors are used concomitantly, symptoms of arterial hypotension and edema should be monitored regularly.

Clarithromycin (inhibitor of the CYP3A4 isoenzyme)

In patients taking clarithromycin and Amlodipine concomitantly, there is an increased risk of decreased blood pressure. Patients receiving such combination therapy are recommended to be under close medical supervision.

Inducers of the CYP3A4 isoenzyme

When inducers of the CYP3A4 isoenzyme are used concomitantly, the concentration of amlodipine may vary. Blood pressure should be monitored, and dose adjustment of amlodipine should be considered during and after concomitant administration, especially with strong inducers of the CYP3A4 isoenzyme (e.g., rifampicin and preparations of St. John’s wort).

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 30°C (86°F).

Shelf Life

The shelf life is 2 years (in blisters), 3 years (in bottles). Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.