Nelminorm^® N (Tablets) Instructions for Use

Marketing Authorization Holder

Micro Labs Limited (India)

ATC Code

C09DA07 (Telmisartan and diuretics)

Active Substances

Hydrochlorothiazide (Rec.INN registered by WHO)

Telmisartan (Rec.INN registered by WHO)

Dosage Form

Nelminorm® N

Tablets 12.5 mg+80 mg: 10, 30, 50, or 100 pcs.

Dosage Form, Packaging, and Composition

Tablets are two-layer (a layer from white to almost white and a layer from pink to reddish-pink), oval, biconvex, with an engraving “TH2” on one side; inclusions are possible.

Excipients: mannitol, meglumine, sodium hydroxide, povidone K-30, crospovidone type A, magnesium stearate, lactose monohydrate, microcrystalline cellulose (PH 101), microcrystalline cellulose (PH 102), corn starch, iron oxide red dye.

10 pcs. – blisters (1) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (5) – cardboard packs.
10 pcs. – blisters (10) – cardboard packs.

Clinical-Pharmacological Group

Antihypertensive drug

Pharmacotherapeutic Group

Antihypertensive combination agent (angiotensin II receptor blocker + diuretic)

Pharmacological Action

Combined antihypertensive drug, which contains the angiotensin II receptor antagonist Telmisartan and the thiazide diuretic Hydrochlorothiazide. The simultaneous use of these components leads to a more pronounced antihypertensive effect than the use of each of them separately.

Telmisartan is a specific angiotensin II receptor antagonist. It has a high affinity for the AT₁ receptor subtype of angiotensin II, through which the action of angiotensin II is realized. Telmisartan displaces angiotensin II from binding to the receptor, without having an agonist effect on this receptor. Telmisartan binds only to the AT₁ receptor subtype of angiotensin II. The binding is long-lasting. Telmisartan has no affinity for other receptors (including AT₂ receptors) of angiotensin. The functional significance of these receptors, as well as the effect of their possible excessive stimulation by angiotensin II, the concentration of which increases with the appointment of telmisartan, has not been studied. Telmisartan leads to a decrease in the concentration of aldosterone in the blood, does not inhibit plasma renin and does not block ion channels. Telmisartan does not inhibit ACE (kininase II), an enzyme that also breaks down bradykinin, so an increase in bradykinin-mediated side effects is not expected.

In patients with arterial hypertension, Telmisartan at a dose of 80 mg completely blocks the hypertensive effect of angiotensin II. The onset of the antihypertensive effect is noted within 3 hours after the first oral intake of telmisartan. The effect persists for 24 hours and remains significant for up to 48 hours. A pronounced antihypertensive effect usually develops after 4 weeks of regular use.

In patients with arterial hypertension, Telmisartan reduces systolic and diastolic blood pressure without affecting heart rate.

In case of abrupt withdrawal of telmisartan, blood pressure gradually returns to baseline without the development of withdrawal syndrome.

Hydrochlorothiazide is a thiazide diuretic, the diuretic effect of which is associated with impaired reabsorption of sodium, chloride, potassium, magnesium ions, and water in the distal nephron; it delays the excretion of calcium ions and uric acid. It has antihypertensive properties; the hypotensive effect develops due to the expansion of arterioles. It has practically no effect on normal blood pressure levels.

The excretion of electrolytes and water begins approximately 2 hours after administration, the maximum effect is reached in 3-6 hours and persists for 6-12 hours. The antihypertensive effect is achieved in 3-4 days of treatment and lasts for 1 week after the end of the drug intake. With long-term treatment, a decrease in blood pressure is achieved with the use of lower doses than those necessary for a diuretic effect. The decrease in blood pressure is accompanied by a slight increase in the glomerular filtration rate, renal vascular resistance and plasma renin activity.

Hydrochlorothiazide, when taken once in high doses, leads to a decrease in plasma volume, glomerular filtration rate, renal blood flow and mean blood pressure. With long-term use in low doses, the blood plasma volume remains reduced, while the minute volume and glomerular filtration rate return to the baseline level preceding the start of treatment. Mean blood pressure and systemic vascular resistance remain reduced. Thiazide diuretics may interfere with breast milk production.

The maximum antihypertensive effect of the Telmisartan+Hydrochlorothiazide combination is usually achieved after 4-8 weeks from the start of treatment.

Pharmacokinetics

The simultaneous use of hydrochlorothiazide and telmisartan does not affect the pharmacokinetics of each of the drug components.

Telmisartan

When taken orally, it is rapidly absorbed from the gastrointestinal tract. Bioavailability is approximately 50%. C_max of telmisartan is reached within 0.5-1.5 hours after application. When taken simultaneously with food, the decrease in AUC ranges from 6% (when used at a dose of 40 mg) to 19% (when used at a dose of 160 mg). After 3 hours of oral administration, the plasma concentration levels out, regardless of food intake. Binding to plasma proteins is significant (more than 99.5%), mainly with albumin and α₁-glycoprotein. V_d is approximately 500 L. Telmisartan is metabolized by conjugation with glucuronic acid. Metabolites are pharmacologically inactive. T_1/2 is more than 20 hours. It is excreted through the intestine unchanged, renal excretion is less than 2%. The total plasma clearance is high (about 900 ml/min).

Pharmacokinetic studies in patients with hepatic insufficiency have shown an increase in absolute bioavailability to almost 100%. In hepatic insufficiency, T_1/2 does not change.

Hydrochlorothiazide

After oral administration, C_max of hydrochlorothiazide is reached within 1-3 hours. Absolute bioavailability is estimated by cumulative renal excretion of hydrochlorothiazide and is about 60%. Binding to plasma proteins is 40-70%. V_d – 0.8±0.3 L/kg. It is not metabolized in the human body and is excreted in the urine almost unchanged. About 60% of the orally taken dose is excreted within 48 hours. Renal clearance is about 250-300 ml/min. T_1/2 – 10-15 hours. There is a difference in plasma concentrations between men and women. Women tend to have a clinically significant increase in plasma concentration of hydrochlorothiazide. In patients with impaired renal function, the excretion rate of hydrochlorothiazide is reduced. Studies involving patients with a CC of 90 ml/min have shown that the T_1/2 of hydrochlorothiazide increases. In patients with reduced renal function, T_1/2 is about 34 hours.

Indications

Arterial hypertension (in case of ineffectiveness of telmisartan or hydrochlorothiazide as monotherapy).

ICD codes

Dosage Regimen

Take orally once a day.

A single dose of the Telmisartan+Hydrochlorothiazide combination ranges from 40 mg/12.5 mg to 80 mg/25 mg.

In patients with severe arterial hypertension, the maximum daily dose of telmisartan is 160 mg/day. This dose was effective and well tolerated.

In patients with mild to moderate hepatic impairment (Child-Pugh class A and B), this combination should not be used at a daily dose of more than 40 mg/12.5 mg.

Adverse Reactions

From the respiratory system respiratory distress syndrome (including pneumonia and pulmonary edema), dyspnea.

From the cardiovascular system arrhythmias, tachycardia, bradycardia, marked decrease in blood pressure (including orthostatic hypotension).

From the nervous system: syncope/fainting, paresthesia, sleep disorders, insomnia, dizziness, anxiety, depression, increased excitability, headache.

From the digestive system: diarrhea, dryness of the oral mucosa, flatulence, abdominal pain, constipation, vomiting, gastritis, decreased appetite, anorexia, hyperglycemia, hypercholesterolemia, pancreatitis, impaired liver function, jaundice (hepatocellular or cholestatic), dyspepsia.

From the skin increased sweating.

From the musculoskeletal system back pain, muscle cramps, myalgia, arthralgia, calf muscle cramps, arthrosis, tendinitis-like symptoms, chest pain.

From the hematopoietic system iron deficiency anemia, aplastic anemia, hemolytic anemia, thrombocytopenia, eosinophilia, leukopenia, neutropenia/agranulocytosis, thrombocytopenia.

From the urinary system renal failure, including acute renal failure, interstitial nephritis, glucosuria.

From the sensory organs visual impairment, transient blurred vision, xanthopsia, acute angle-closure glaucoma, acute myopia.

From the reproductive system impotence.

Infections sepsis, including fatal cases, upper respiratory tract infections (bronchitis, pharyngitis, sinusitis), urinary tract infections (including cystitis), inflammation of the salivary glands.

From the metabolism: increased plasma creatinine concentration, increased activity of liver enzymes, increased activity of CPK, increased blood uric acid concentration, hypertriglyceridemia, hypokalemia, hyperkalemia, hyponatremia, hyperuricemia, decreased blood volume, hypoglycemia (in patients with diabetes mellitus), impaired glucose tolerance, decreased blood hemoglobin level.

Allergic reactions angioedema (including fatal cases), erythema, skin itching, rash, anaphylactic reactions, eczema, drug rash, toxic epidermal necrolysis, lupus-like reactions, exacerbation or intensification of systemic lupus erythematosus symptoms, necrotizing vasculitis, systemic vasculitis, photosensitivity reaction, recurrence of systemic lupus erythematosus, vasculitis.

Other flu-like syndrome, fever, weakness.

Contraindications

Obstructive biliary tract diseases; severe hepatic impairment (Child-Pugh class C); severe renal impairment (CC <30 ml/min); refractory hypokalemia, hypercalcemia; simultaneous use with aliskiren in patients with diabetes mellitus and renal failure (GFR <60 ml/min/1.73 m²); age under 18 years; pregnancy; lactation (breastfeeding) period; hypersensitivity to telmisartan, hydrochlorothiazide or other sulfonamide derivatives.

With caution: bilateral renal artery stenosis or stenosis of the artery of a single kidney; impaired liver function or progressive liver disease (Child-Pugh class A and B); reduced blood volume due to previous diuretic therapy, salt restriction, diarrhea or vomiting; hyperkalemia; condition after kidney transplantation (no experience of use); chronic heart failure III-IV FC according to NYHA classification; stenosis of the aortic and mitral valve; idiopathic hypertrophic subaortic stenosis; hypertrophic obstructive cardiomyopathy; diabetes mellitus; primary aldosteronism; gout; angle-closure glaucoma (due to the presence of hydrochlorothiazide in the composition).

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Use in Hepatic Impairment

Contraindication: severe hepatic impairment (Child-Pugh class C).

Use in Renal Impairment

Contraindication: severe renal impairment (CC <30 ml/min); refractory hypokalemia, hypercalcemia; simultaneous use with aliskiren in patients with diabetes mellitus and renal failure (GFR <60 ml/min/1.73 m²).

Geriatric Use

The drug is approved for use in elderly patients.

Special Precautions

In some patients, due to the suppression of the RAAS activity, especially with the simultaneous use of drugs acting on this system, renal function is impaired (including acute renal failure). Therefore, therapy accompanied by such a dual blockade of the RAAS (for example, when adding an ACE inhibitor or a direct renin inhibitor – aliskiren to angiotensin II receptor antagonists) should be carried out strictly individually and with regular monitoring of renal function (including periodic monitoring of potassium and creatinine levels in the blood serum).

The use of thiazide diuretics in patients with impaired renal function may lead to azotemia. Periodic monitoring of renal function is recommended.

In patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney, when using drugs that affect the RAAS, the risk of developing severe arterial hypotension and renal failure increases.

In patients with impaired liver function or progressive liver disease, this combination should be used with caution, since even minor changes in the water-electrolyte balance can contribute to the development of hepatic coma.

In patients with diabetes mellitus, a change in the dose of insulin or oral hypoglycemic agents may be required. During therapy with thiazide diuretics, latent diabetes mellitus may manifest.

In some cases, when using thiazide diuretics, the development of hyperuricemia and exacerbation of gout is possible.

In patients with diabetes mellitus and additional cardiovascular risk, for example, in patients with diabetes mellitus and coronary artery disease, when using drugs that lower blood pressure, such as angiotensin II receptor antagonists or ACE inhibitors, the risk of fatal myocardial infarction and sudden cardiovascular death may increase. In patients with diabetes mellitus, coronary artery disease may be asymptomatic and therefore may be undiagnosed. Before starting the use of this combination, appropriate diagnostic studies, including an exercise test, should be performed to detect and treat coronary artery disease.

Hydrochlorothiazide, being a sulfonamide derivative, can cause an idiosyncratic reaction in the form of acute transient myopia and acute angle-closure glaucoma. The symptoms of these disorders are an unexpected decrease in visual acuity or eye pain, which typically occur within a few hours to several weeks after starting the drug. If left untreated, acute angle-closure glaucoma can lead to vision loss. The main treatment is to discontinue hydrochlorothiazide as soon as possible. It should be borne in mind that if intraocular pressure remains uncontrolled, emergency conservative or surgical treatment may be required. Risk factors for the development of acute angle-closure glaucoma may include a history of allergy to sulfonamides or penicillin.

Thiazide diuretics, including Hydrochlorothiazide, can cause disturbances in water-electrolyte balance and acid-base status (hypokalemia, hyponatremia and hypochloremic alkalosis). Signs that are alarming for these disorders are dry oral mucosa, feeling of thirst, general weakness, drowsiness, feeling of restlessness, myalgia or convulsive twitching of the calf muscles (cramps), muscle weakness, marked decrease in blood pressure, oliguria, tachycardia and such gastrointestinal disorders as nausea or vomiting. During treatment with this combination, periodic monitoring of serum electrolyte levels is necessary.

When using this combination, the risk of hypokalemia is more likely in patients with liver cirrhosis, with increased diuresis, when following a salt-free diet, as well as in the case of simultaneous use of glucocorticoids and mineralocorticoids or corticotropin; risk factors for the development of hyperkalemia include renal and/or heart failure and diabetes mellitus.

Thiazide diuretics can reduce the renal excretion of calcium and cause (in the absence of obvious disorders of calcium metabolism) a transient and slight increase in serum calcium levels. A more pronounced hypercalcemia may be a sign of latent hyperparathyroidism. Before assessing the function of the parathyroid glands, thiazide diuretics should be discontinued.

Thiazide diuretics have been shown to increase the renal excretion of magnesium, which can lead to hypomagnesemia.

In patients with coronary artery disease, the use of any antihypertensive agent, in case of an excessive decrease in blood pressure, can lead to myocardial infarction or stroke.

Effect on the ability to drive vehicles and mechanisms

During the treatment period, the possibility of developing dizziness and drowsiness should be taken into account, which requires caution.

Drug Interactions

Telmisartan

Other antihypertensive agents – enhancement of the hypotensive effect is possible.

Lithium preparations – a reversible increase in lithium concentration in the blood, accompanied by toxic phenomena, has rarely been observed. With the simultaneous use of lithium preparations and angiotensin II receptor antagonists, it is recommended to determine the lithium content in the blood;

NSAIDs, including acetylsalicylic acid in doses used as an anti-inflammatory agent, COX-2 inhibitors and non-selective NSAIDs – the development of acute renal failure in patients with reduced blood volume is possible. Drugs affecting the RAAS may have a synergistic effect. In patients receiving NSAIDs and Telmisartan, blood volume should be compensated at the beginning of treatment and renal function should be examined. A decrease in the effect of antihypertensive agents, such as Telmisartan, by inhibiting the vasodilatory effect of prostaglandins was observed with concomitant treatment with NSAIDs. No clinically significant effect was detected with the simultaneous use of telmisartan with ibuprofen or paracetamol.

Digoxin – an increase in the average plasma concentration of digoxin by an average of 20% (in one case by 39%) has been noted. When telmisartan and digoxin are prescribed concomitantly, it is advisable to periodically determine the concentration of digoxin in the blood.

Hydrochlorothiazide

Ethanol, barbiturates, opioid analgesics – risk of orthostatic hypotension.

Oral hypoglycemic agents and insulin – dose adjustment of oral hypoglycemic agents and insulin may be required.

Metformin – there is a risk of lactic acidosis.

Cholestyramine and colestipol – the absorption of hydrochlorothiazide is impaired in the presence of anion exchange resins.

Cardiac glycosides – the risk of hypokalemia or hypomagnesemia caused by thiazide diuretics, and the development of arrhythmias caused by cardiac glycosides, is increased.

Pressor amines (e.g., norepinephrine) – the effect of pressor amines may be reduced.

Non-depolarizing muscle relaxants (e.g., tubocurarine chloride) – Hydrochlorothiazide may enhance the effect of non-depolarizing muscle relaxants;

Antigout agents – an increase in serum uric acid concentration is possible, so dose changes of uricosuric agents may be required. The use of thiazide diuretics increases the frequency of hypersensitivity reactions to allopurinol.

Calcium preparations – thiazide diuretics may increase serum calcium levels due to decreased renal excretion. If calcium preparations are required, blood calcium levels should be monitored regularly and the dose of calcium preparations adjusted if necessary.

Beta-blockers and diazoxide – thiazide diuretics may enhance hyperglycemia caused by beta-blockers and diazoxide;

M-cholinoblockers (e.g., atropine, biperiden) – decreased gastrointestinal motility, increased bioavailability of thiazide diuretics.

Amantadine – thiazide diuretics may increase the risk of adverse effects caused by amantadine.

Cytotoxic agents (e.g., cyclophosphamide, methotrexate) – decreased renal excretion of cytotoxic agents and enhancement of their myelosuppressive action.

NSAIDs – concomitant use with thiazide diuretics may lead to a reduction in the diuretic and antihypertensive effect.

Agents that lead to potassium loss and hypokalemia (e.g., potassium-excreting diuretics, laxatives; gluco- and mineralocorticoids; corticotropin; amphotericin B; carbenoxolone; benzylpenicillin, acetylsalicylic acid derivatives) – enhancement of the hypokalemic effect. The hypokalemia caused by hydrochlorothiazide is compensated by the potassium-sparing effect of telmisartan.

Potassium-sparing diuretics, potassium preparations, other agents capable of increasing serum potassium (e.g., heparin) or substitution of sodium in table salt with potassium salts – hyperkalemia may develop. Periodic monitoring of plasma potassium levels is recommended in cases where the Telmisartan+Hydrochlorothiazide combination is used concomitantly with drugs that can cause hypokalemia, as well as with drugs that can increase serum potassium levels.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.