Artinova^® AM (Tablets) Instructions for Use

Marketing Authorization Holder

Sun Pharmaceutical Industries, Ltd. (India)

ATC Code

C09DB01 (Valsartan and amlodipine)

Active Substances

Valsartan (Rec.INN registered by WHO)

Amlodipine (Rec.INN registered by WHO)

Dosage Forms

	Artinova® AM	Film-coated tablets, 5 mg+80 mg: 28 or 30 pcs.
		Film-coated tablets, 5 mg+160 mg: 28 or 30 pcs.
		Film-coated tablets, 10 mg+160 mg: 28 or 30 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets brownish-yellow, oval, biconvex; engraved “AV1” on one side and smooth on the other; on the break: core – white or almost white mass, coated with a brownish-yellow film coating.

Excipients: microcrystalline cellulose (Avicel PH101) – 56.516 mg + 69.55 mg, crospovidone – 10.5 mg, colloidal silicon dioxide – 3 mg + 5 mg, magnesium stearate – 3 mg + 1.5 mg + 1.5 mg, pregelatinized starch – 35 mg, talc – 2.5 mg.

Film coating composition: opadry yellow (03F82330)- 6.875 mg;
Composition of opadry yellow (03F82330) hypromellose 6 cP- 60%, iron oxide yellow- 15%, macrogol-4000- 10%, titanium dioxide- 10%, talc- 5%

7 pcs. – blisters made of aluminum foil (4) – cardboard packs.
10 pcs. – blisters made of aluminum foil (3) – cardboard packs.

Film-coated tablets brownish-yellow, oval, biconvex; engraved “AV2” on one side and smooth on the other; on the break: core – light yellow or yellow mass, coated with a brownish-yellow film coating.

Excipients: microcrystalline cellulose (Avicel PH101) – 119.966 mg + 138.9 mg, crospovidone – 21 mg, colloidal silicon dioxide – 6 mg + 10 mg, magnesium stearate – 6 mg + 3 mg + 3 mg, pregelatinized starch – 70 mg, talc – 5 mg.

Film coating composition: opadry yellow (03F82330)- 13.75 mg;
Composition of opadry yellow (03F82330) hypromellose 6 cP- 60%, iron oxide yellow- 15%, macrogol-4000- 10%, titanium dioxide- 10%, talc- 5%

7 pcs. – blisters made of aluminum foil (4) – cardboard packs.
10 pcs. – blisters made of aluminum foil (3) – cardboard packs.

Film-coated tablets brownish-pink, oval, biconvex; engraved “AV3” on one side and smooth on the other; on the break: core – white or almost white mass, coated with a brownish-pink film coating.

Excipients: microcrystalline cellulose (Avicel PH101) – 113.032 mg + 139.1 mg, crospovidone – 21 mg, colloidal silicon dioxide – 6 mg + 10 mg, magnesium stearate – 6 mg + 3 mg + 3 mg, pregelatinized starch – 70 mg, talc – 5 mg.

Film coating composition: opadry orange (03F83059)- 13.75 mg;
Composition of opadry orange (03F83059) hypromellose 6 cP- 62.5%, titanium dioxide- 20.97%, macrogol-4000- 10%, talc- 5%, iron oxide yellow- 1.38%, iron oxide red – 0.15%

7 pcs. – blisters made of aluminum foil (4) – cardboard packs.
10 pcs. – blisters made of aluminum foil (3) – cardboard packs.

Clinical-Pharmacological Group

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

Pharmacotherapeutic Group

Antihypertensive combination agent (angiotensin II receptor blocker + CCB)

Pharmacological Action

A combined antihypertensive drug containing: amlodipine (a dihydropyridine derivative) and valsartan (an angiotensin II receptor antagonist). The combination of these components has a mutually complementary antihypertensive effect, leading to a more pronounced reduction in blood pressure than when used separately.

Clinical efficacy of the amlodipine/valsartan combination has been proven in patients with mild to moderate arterial hypertension (mean diastolic BP ≥95 mm Hg and <110 mm Hg) without complications compared to placebo. The level of sitting BP reduction in arterial hypertension with diastolic BP ≥110 mm Hg and <120 mm Hg is comparable to the use of an ACE inhibitor and thiazide diuretic combination. When using the amlodipine/valsartan combination, comparable BP control is achieved with a lower likelihood of developing peripheral edema in patients with previously achieved BP control and significant peripheral edema during amlodipine therapy.

When taking the amlodipine/valsartan combination in a single dose, the hypotensive effect persists for 24 hours. The antihypertensive effect is long-lasting. Sudden discontinuation of the drug is not accompanied by a sharp increase in BP (no withdrawal syndrome). Therapeutic efficacy does not depend on the patient’s age, sex, race, or BMI.

Amlodipine – a dihydropyridine derivative, a calcium channel blocker. It has antianginal and antihypertensive effects. It inhibits the transmembrane transition of calcium ions into cardiomyocytes and vascular smooth muscle cells. The antihypertensive effect of amlodipine is due to a direct relaxing effect on vascular smooth muscle cells. The mechanism of the antianginal action of amlodipine is not fully understood; it is presumably associated with the following effects: causes dilation of peripheral arterioles, reducing total peripheral resistance (afterload), which leads to a decrease in myocardial oxygen demand; causes dilation of coronary arteries and arterioles in both intact and ischemic areas of the myocardium, increasing oxygen supply to the myocardium, including in patients with Prinzmetal’s angina. Amlodipine reduces the severity of left ventricular hypertrophy. It does not affect myocardial contractility and conductivity, does not cause a reflex increase in heart rate, inhibits platelet aggregation, increases GFR, and has a weak natriuretic effect.

In patients with arterial hypertension, taking amlodipine once daily provides a clinically significant reduction in BP (in supine and standing positions) over 24 hours. The antihypertensive effect develops slowly, so the development of acute arterial hypotension is uncharacteristic. In patients with angina, taking amlodipine once daily increases exercise tolerance, time to onset of angina attack and to ischemic ST-segment depression, reduces the frequency of angina attacks and the need for nitroglycerin intake (short-acting forms).

The clinical efficacy of amlodipine has been proven in patients with stable exertional angina, vasospastic angina, and angiographically confirmed coronary artery disease.

Amlodipine does not have an undesirable effect on lipid metabolism and does not cause changes in the plasma lipid profile. Amlodipine can be used in patients with bronchial asthma, diabetes mellitus, and gout.

After a single oral dose, the effect of amlodipine begins within 2-4 hours and lasts for 24 hours. The maximum hypotensive effect is achieved no earlier than 4 weeks from the start of taking the drug. The hemodynamic effects of the drug remain unchanged during long-term use.

Valsartan – a selective angiotensin II receptor antagonist (type AT₁) for oral administration. Selectively blocks AT₁ subtype receptors, which are responsible for the effects of angiotensin II. An increase in plasma angiotensin II concentration due to blockade of AT₁ receptors under the action of valsartan may stimulate unblocked AT₂ subtype receptors, which counteract the effects of AT₁ receptor stimulation. Valsartan has no agonistic activity towards AT₁ receptors. The affinity of valsartan for AT₁ subtype receptors is approximately 20,000 times higher than for AT₂ subtype receptors.

Valsartan does not interact with or block receptors of other hormones or ion channels involved in the regulation of cardiovascular functions.

Valsartan does not inhibit ACE, also known as kininase II, which converts angiotensin I to angiotensin II and breaks down bradykinin. Due to the lack of effect on ACE, the effects of bradykinin or substance P are not potentiated, so the development of dry cough is unlikely when using angiotensin II receptor antagonists. It has been proven that the incidence of dry cough during treatment with valsartan is significantly lower than with the use of ACE inhibitors. In the treatment of arterial hypertension, Valsartan reduces BP without affecting heart rate.

After a single oral dose of valsartan, the hypotensive effect develops within 2 hours, and the maximum reduction in BP is achieved within 4-6 hours. The antihypertensive effect of valsartan persists for 24 hours after its intake. With repeated use of valsartan, the maximum reduction in BP, regardless of the dose, is achieved after 2-4 weeks and is maintained at the achieved level during long-term therapy. Sudden discontinuation of valsartan is not accompanied by a significant increase in BP or other adverse events (withdrawal syndrome).

Pharmacokinetics

The pharmacokinetics of amlodipine and valsartan are linear.

Amlodipine/Valsartan

After oral administration of the amlodipine/valsartan combination, C_max of valsartan and amlodipine in plasma is reached after 3 hours and 6-8 hours, respectively. The rate and extent of absorption are equivalent to the bioavailability of valsartan and amlodipine when taken separately.

Amlodipine

After oral administration, amlodipine is slowly and almost completely absorbed from the gastrointestinal tract. Simultaneous food intake does not affect the absorption of amlodipine. C_max in plasma is reached 6-12 hours after administration. The mean absolute bioavailability is 64-80%. The mean V_d is 21 L/kg of body weight, indicating that most of the amlodipine is in the tissues, and a smaller part is in the blood. Most of the amlodipine in the blood (97.5%) is bound to plasma proteins. C_ss in plasma are reached after 7-8 days of continuous amlodipine use. Amlodipine crosses the BBB and the placental barrier.

Amlodipine undergoes slow but active metabolism in the liver in the absence of a significant first-pass effect. Metabolites do not have significant pharmacological activity.

After a single dose of amlodipine, T_1/2 ranges from 35 to 50 hours; with repeated use, it is approximately 45 hours. About 60% of the orally administered dose is excreted by the kidneys mainly as metabolites, 10% – unchanged, 20-25% – through the intestine with bile. The total clearance of amlodipine is 0.116 ml/s/kg (7 ml/min/kg, 0.42 L/h/kg). Amlodipine is not removed by hemodialysis.

Prolongation of T_1/2 in patients with hepatic insufficiency suggests that with long-term use, the accumulation of amlodipine in the body will be higher (increases to 60 hours).

Valsartan

After oral administration of valsartan, C_max is reached after 2-3 hours. The mean absolute bioavailability is 23%. When valsartan is taken with food, a decrease in bioavailability (by AUC value) of approximately 40% is noted, and C_max – approximately 50%. Approximately 8 hours after oral administration, plasma concentrations of valsartan in the group of patients taking the drug with food and in the group taking the drug on an empty stomach level out. The reduction in AUC is not clinically significant, so Valsartan can be taken regardless of food intake.

V_d of valsartan at steady state after IV administration is about 17 L, indicating no extensive distribution of valsartan in tissues. Valsartan is largely bound to serum proteins (94-97%), mainly to serum albumin.

Valsartan does not undergo significant metabolism. About 20% of the administered dose is determined in plasma as metabolites. The hydroxyl metabolite is determined in plasma in low concentrations (less than 10% of the AUC of valsartan). This metabolite is pharmacologically inactive.

Valsartan is excreted in two phases: α-phase with T_1/2α less than 1 hour and β-phase with T_1/2β – about 9 hours. Valsartan is excreted mainly unchanged through the intestine (about 83%) and by the kidneys (about 13%). After IV administration, the plasma clearance of valsartan is about 2 L/h and its renal clearance is 0.62 L/h (about 30% of total clearance). The T_1/2 of valsartan is 6 hours.

On average, in patients with mild (5-6 points on the Child-Pugh scale) and moderate (7-9 points on the Child-Pugh scale) hepatic impairment, the bioavailability (by AUC value) of valsartan doubles compared to healthy volunteers of the corresponding age, sex, and body weight.

Indications

• Arterial hypertension in patients for whom combination therapy with amlodipine and valsartan is indicated.

ICD codes

Dosage Regimen

The drug should be taken orally, once daily, regardless of meals, with a small amount of water.

The recommended daily dose is 1 tablet of the drug containing the amlodipine/valsartan combination in a dose of 5 mg/80 mg, 5 mg/160 mg, 10 mg/160 mg, 5 mg/320 mg or 10 mg/320 mg.

The initial dose of the drug is 5 mg/80 mg once daily. The dose can be increased after 1-2 weeks from the start of therapy.

The maximum daily dose is 5 mg/320 mg (in terms of valsartan) or 10 mg/160 mg (in terms of amlodipine) or 10 mg/320 mg.

In patients with impaired renal function (CrCl >30 ml/min), adjustment of the initial dose of the drug is not required.

Patients with impaired liver function should use the drug with caution. The maximum daily dose of valsartan in mild to moderate hepatic insufficiency is 80 mg. The drug is contraindicated in patients with severe hepatic insufficiency, biliary cirrhosis and cholestasis.

In elderly patients, dose adjustment is not required.

Adverse Reactions

Classification of the frequency of side effects according to WHO: very common (≥1/10), common (from ≥1/100 to <1/10), uncommon (from ≥1/1000 to <1/100), rare (from ≥1/10,000 to <1/1000), very rare (from <1/10,000), frequency unknown (cannot be estimated from the available data).

Amlodipine/Valsartan

Infections and infestations: common – influenza.

Metabolism and nutrition disorders: common – hypokalemia; uncommon – hypercalcemia, hyperlipidemia, hyperuricemia, hyponatremia.

Nervous system disorders common – headache; uncommon – coordination abnormal, dizziness, postural dizziness, paresthesia, somnolence; rare – anxiety.

Eye disorders uncommon – vision blurred; rare – visual impairment.

Ear and labyrinth disorders: uncommon – vertigo; rare – tinnitus.

Cardiac disorders uncommon – palpitations, tachycardia, orthostatic hypotension; rare – marked decrease in blood pressure, syncope.

Respiratory, thoracic and mediastinal disorders common – nasopharyngitis; uncommon – cough, pharyngolaryngeal pain.

Gastrointestinal disorders: uncommon – diarrhea, nausea, abdominal discomfort, upper abdominal pain, constipation, dry mouth.

Skin and subcutaneous tissue disorders: uncommon – erythema, skin rash; rare – exanthema, hyperhidrosis, pruritus.

Musculoskeletal and connective tissue disorders uncommon – arthralgia, joint swelling; rare – muscle spasms, feeling of heaviness in the whole body.

Renal and urinary disorders rare – pollakiuria, polyuria.

Reproductive system and breast disorders: rare – erectile dysfunction.

Immune system disorders: rare – hypersensitivity.

General disorders and administration site conditions: common – asthenia, fatigue, face edema, feeling of skin flushing, edema, peripheral edema, puffiness; uncommon – anorexia, back pain.

In patients receiving the amlodipine/valsartan combination, peripheral edema occurred less frequently (5.8%) than in patients receiving amlodipine monotherapy (9%).

Amlodipine

Common somnolence, dizziness, palpitations, abdominal pain, nausea, ankle edema.

Uncommon insomnia, mood changes (including anxiety), depression, tremor, taste disturbance, syncope, hypoesthesia, visual disturbances (including diplopia), tinnitus, marked decrease in blood pressure, dyspnea, rhinitis, vomiting, dyspepsia, alopecia, purpura, skin discoloration, hyperhidrosis, pruritus, exanthema, myalgia, muscle cramps, pain, micturition disorder, urinary frequency, impotence, gynecomastia, chest pain, malaise, weight increased, weight decreased.

Rare confusion.

Very rare leukopenia, thrombocytopenia, allergic reactions, hyperglycemia, muscle hypertonia, peripheral neuropathy, myocardial infarction, arrhythmias (including bradycardia, ventricular tachycardia and atrial fibrillation), vasculitis, pancreatitis, gastritis, gingival hyperplasia, hepatitis, jaundice, increased liver enzyme activity (most often due to cholestasis), angioedema, erythema multiforme, urticaria, exfoliative dermatitis, Stevens-Johnson syndrome, photosensitivity.

Isolated cases of extrapyramidal syndrome have been described.

Valsartan

Frequency unknown decrease in hemoglobin and hematocrit, neutropenia, thrombocytopenia, increased serum potassium, increased activity of liver enzymes, increased plasma bilirubin concentration, increased plasma creatinine concentration, renal impairment including renal failure, angioedema, myalgia, vasculitis, hypersensitivity including serum sickness.

Contraindications

• Severe hepatic impairment (more than 9 points on the Child-Pugh scale);
• Biliary cirrhosis and cholestasis;
• Severe renal impairment (CrCl <30 ml/min);
• Use in patients on hemodialysis;
• Severe arterial hypotension (systolic BP <90 mm Hg);
• Collapse, shock (including cardiogenic shock);
• Obstruction of the left ventricular outflow tract (including hypertrophic obstructive cardiomyopathy and severe aortic stenosis);
• Hemodynamically unstable heart failure after acute myocardial infarction;
• Concomitant use with aliskiren in patients with diabetes mellitus or renal impairment (CrCl less than 60 ml/min);
• Primary hyperaldosteronism;
• Pregnancy;
• Lactation (breastfeeding);
• Hypersensitivity to amlodipine, other dihydropyridine derivatives, valsartan or other components of the drug.

The safety of the drug in patients after kidney transplantation, as well as in children and adolescents under 18 years of age has not been established.

This combination should be used with caution in mild (5-6 points on the Child-Pugh scale) and moderate (7-9 points on the Child-Pugh scale) hepatic impairment; obstructive biliary diseases; mild and moderate renal impairment (CrCl 30-50 ml/min); unilateral or bilateral renal artery stenosis or stenosis of the artery of a single kidney; chronic heart failure NYHA class III-IV; hyperkalemia; hyponatremia; salt-restricted diet; reduced blood volume (including due to diarrhea, vomiting); in patients with hereditary angioedema, or angioedema associated with previous therapy with angiotensin II receptor antagonists; in patients with mild and moderate mitral and aortic stenosis.

Use in Pregnancy and Lactation

The use of this combination is contraindicated during pregnancy and lactation.

Use in Hepatic Impairment

The use of the drug is contraindicated in severe hepatic impairment (more than 9 points on the Child-Pugh scale), biliary cirrhosis and cholestasis.

This combination should be used with caution in mild (5-6 points on the Child-Pugh scale) and moderate (7-9 points on the Child-Pugh scale) hepatic impairment; obstructive biliary diseases.

Use in Renal Impairment

The use of the drug is contraindicated in severe renal impairment (CrCl <30 ml/min); in patients on hemodialysis.

This combination should be used with caution in mild and moderate renal impairment (CrCl 30-50 ml/min); unilateral or bilateral renal artery stenosis or stenosis of the artery of a single kidney.

The safety of the drug in patients after kidney transplantation has not been established.

Pediatric Use

The safety of the drug in children and adolescents under 18 years of age has not been established.

Geriatric Use

No dose adjustment is required in elderly patients.

Special Precautions

In patients with uncomplicated arterial hypertension receiving therapy with the amlodipine/Valsartan combination, severe arterial hypotension was observed in 0.4% of cases.

In patients with activated RAAS (for example, in patients with dehydration and/or hyponatremia taking high doses of diuretics), symptomatic arterial hypotension may develop when taking angiotensin II receptor antagonists. Before starting treatment, sodium levels and/or blood volume should be restored, in particular by reducing diuretic doses, or therapy should be started under close medical supervision.

If a pronounced decrease in BP develops, the patient should be placed in a horizontal position with a low headboard and, if necessary, an intravenous infusion of 0.9% sodium chloride solution should be administered. Therapy with the drug can be continued after hemodynamic parameters have stabilized.

Caution should be exercised when used concomitantly with potassium-sparing diuretics, potassium preparations, dietary supplements containing potassium, or other drugs that can increase plasma potassium levels (for example, heparin). Plasma potassium levels should be monitored regularly.

The drug should be used with caution in patients with arterial hypertension and unilateral or bilateral renal artery stenosis or stenosis of the artery of a single kidney, given the possibility of increased serum concentrations of urea and creatinine.

In patients with moderate renal impairment, it is recommended to monitor plasma potassium levels and creatinine concentrations.

Given the involvement of the RAAS in primary hyperaldosteronism, patients in this group should not be prescribed angiotensin II receptor antagonists, including Valsartan.

Among patients with angioedema (including laryngeal and vocal cord edema causing airway obstruction and/or edema of the face, lips, pharynx and/or tongue) during therapy with the drug, there were reports of a history of angioedema, including with ACE inhibitors. If angioedema develops, the drug should be discontinued immediately and the possibility of re-administration should be excluded.

In patients whose renal function may depend on RAAS activity (for example, in severe chronic heart failure), therapy with ACE inhibitors and angiotensin II receptor antagonists is accompanied by oliguria and/or increased azotemia, and in rare cases, by acute renal failure and/or death. Such outcomes have been described with the use of valsartan. Renal function should always be assessed in patients with chronic heart failure or a history of myocardial infarction.

In patients with chronic heart failure of non-ischemic etiology NYHA class III-IV, the use of amlodipine was accompanied by an increased incidence of pulmonary edema compared with placebo, with no significant difference in the frequency of worsening chronic heart failure between the two groups. Calcium channel blockers, including amlodipine, should be used with caution in patients with chronic heart failure, as an increased risk of cardiovascular complications and death is possible.

The amlodipine/Valsartan combination has been studied only in patients with arterial hypertension.

Effect on ability to drive vehicles and machinery

Caution should be exercised when driving vehicles and other technical devices requiring increased concentration and speed of psychomotor reactions, as dizziness, fatigue and nausea may develop.

Drug Interactions

Amlodipine/Valsartan

Other antihypertensive drugs (for example, alpha-blockers, diuretics) and drugs with hypotensive effects (for example, tricyclic antidepressants, alpha-blockers for the treatment of benign prostatic hyperplasia) may enhance the antihypertensive effect.

Amlodipine

Concomitant use with grapefruit or grapefruit juice is not recommended, given the possibility of increased bioavailability in some patients and enhanced antihypertensive effect.

Concomitant use with strong or moderate inhibitors of the CYP3A4 isoenzyme (protease inhibitors, verapamil or diltiazem, antifungal agents from the azole group, antibiotics from the macrolide group, such as erythromycin or clarithromycin) may lead to a significant increase in the systemic exposure of amlodipine. In elderly patients, these changes are clinically significant, so medical supervision and dose adjustment are necessary.

Caution should be exercised when used concomitantly with inducers of the CYP3A4 isoenzyme (anticonvulsants (for example, carbamazepine, phenobarbital, phenytoin, fosphenytoin, primidone), rifampicin, herbal preparations containing St. John’s wort), as a decrease in the plasma concentration of amlodipine is possible.

Concomitant repeated use of amlodipine 10 mg and simvastatin 80 mg increases the exposure of simvastatin by 77% compared with simvastatin monotherapy. Patients receiving amlodipine are recommended to use simvastatin at a dose not exceeding 20 mg/day.

In experimental studies in animals, cases of fatal ventricular fibrillation and cardiovascular failure associated with hyperkalemia were observed after oral administration of verapamil and intravenous administration of dantrolene. Given the risk of hyperkalemia, concomitant use of calcium channel blockers, including amlodipine, should be avoided in patients prone to malignant hyperthermia.

Clinical studies have not revealed significant interactions with thiazide diuretics, alpha-blockers, beta-blockers, ACE inhibitors, long-acting nitrates, sublingual nitroglycerin, digoxin, warfarin, atorvastatin, sildenafil, Maalox (aluminum- or magnesium-containing antacids, simethicone), cimetidine, NSAIDs, antibiotics and oral hypoglycemic drugs.

Valsartan

Concomitant use of angiotensin II receptor antagonists, including Valsartan, or ACE inhibitors with aliskiren is contraindicated in patients with diabetes mellitus and renal impairment (CrCl less than 60 ml/min).

Concomitant use with lithium preparations is not recommended, as a reversible increase in plasma lithium concentration and the development of intoxication are possible. If concomitant use with lithium preparations is necessary, plasma lithium concentrations should be carefully monitored.

If concomitant use with drugs affecting potassium levels (potassium-sparing diuretics, potassium preparations, potassium-containing dietary supplements and other drugs and substances that can increase serum potassium levels (for example, heparin)) is necessary, it is recommended to monitor plasma potassium levels.

Concomitant use with NSAIDs, including selective COX-2 inhibitors, acetylsalicylic acid at a dose of more than 3 g/day and non-selective NSAIDs may lead to a weakening of the antihypertensive effect, an increased risk of renal impairment and an increase in plasma potassium levels. At the start of therapy, renal function should be assessed and water-electrolyte balance disorders should be corrected.

According to in vitro studies, Valsartan is a substrate for the OATP1B1 and MRP2 transport proteins. Concomitant use of valsartan with inhibitors of the OATP1B1 transport protein (for example, rifampicin, cyclosporine) and inhibitors of the MRP2 transport protein (for example, ritonavir) may increase the systemic exposure of valsartan (C_max and AUC). This should be taken into account at the start and end of concomitant therapy.

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.