Аккузид®

General characteristics. Structure:

International unlicensed or grouping name: the hydrochlorothiazide + hinaprit

Active agents: Hinaprila a hydrochloride of 10,832 mg, 21,664 mg, 21,664 mg ( 10,00 mg,    20,00 mg, 20,00 mg of a hinapril are equivalent), a hydrochlorothiazide of 12,50 mg, 12,50 mg, 25,00 mg;

Excipients: lactoses monohydrate, magnesium a carbonate, povidone - K25, кросповидон, magnesium stearate, a film cover - Opadray pink OY-S-6937 (ferrous oxide yellow, dye ferrous oxide red contains a gipromelloza, a hypro rod, titanium dioxide, a macrogoal-400, dye), wax grassy.

Description. Dosage of 12,5 mg + 10 mg: oval, biconvex tablets, film coated pink color with risky on both parties and marking of "PD 222" on one party.

Dosage of 12,5 mg + 20 mg: triangular, biconvex tablets, film coated pink color with risky and marking of "PD 220" on one party.

Dosage of 25 mg + 20 mg: round, biconvex tablets, film coated pink color with marking of "PD 223" on one party.

Pharmacological properties:

Pharmacodynamics. Аккузид® – the combined drug which part are inhibitor of an angiotensin-converting enzyme (APF) – hinaprit also thiazide diuretic – a hydrochlorothiazide.

Hinapril represents the enzyme catalyzing transformation of angiotensin I into angiotensin II which has vasoconstrictive effect and controls a tone of vessels, including due to stimulation of secretion of Aldosteronum bark of adrenal glands. Hinapril inhibits circulating and fabric APF and causes decrease in angiotonic activity and secretion of Aldosteronum. Elimination of negative influence of angiotensin II on secretion of a renin on a feedback mechanism leads to increase in activity of a renin of a blood plasma. At the same time the lowering of arterial pressure (ABP) is followed by reduction of the general peripheric vascular resistance (GPVR) and resistance of renal vessels while changes of the heart rate (HR), cordial emission, a renal blood-groove, a glomerular filtration rate and filtrational fraction are insignificant or are absent. Besides, hinaprit reduces potassium removal a little, caused by a hydrochlorothiazide which due to the diuretic action also increases activity of a renin of a blood plasma, secretion of Aldosteronum, reduces the content of potassium in blood serum and increases its excretion kidneys.

Hydrochlorothiazide – the diuretic having direct effect on kidneys, increasing removal of sodium, chlorides, liquids, and also potassium and hydrocarbonates, and reducing calcium removal. At prolonged use decrease in OPSS is noted. Thus, use of a combination of a hinapril and hydrochlorothiazide leads to more expressed decrease in the ABP, than therapy by each drug separately.

Anti-hypertensive action of a hinapril develops during 1 h after intake, reaches a maximum in 2–4 h and the current of 24 h at prolonged treatment remains. In certain cases achievement of the maximum anti-hypertensive effect requires not less than 2 weeks of therapy.

Diuretic action of a hydrochlorothiazide develops during 2 h, reaches a maximum approximately in 4 h and about 6-12 h remain.

Pharmacokinetics. Hinapril and a hydrochlorothiazide do not influence indicators of pharmacokinetics of each other. Concentration of a hinapril in a blood plasma at intake reaches a maximum during 1 h Hinapril quickly is metabolized to a hinaprilat by eliminating of radio group (the main metabolite – dibasic acid hinaprit), which is the APF powerful inhibitor.

Taking into account removal of a hinapril and its metabolites kidneys extent of absorption makes about 60%. About 38% of the dose of a hinapril accepted inside circulate in a blood plasma in the form of a hinaprilat. The elimination half-life (T1/2) of a hinapril makes about 1 h of a blood plasma. Concentration of a hinaprilat in a blood plasma reaches a maximum approximately in 2 h after intake of a hinapril. Hinaprilat is brought generally by kidneys, T1/2 - about 3 h. About 97% of a hinapril and a hinaprilat circulate in a blood plasma in the look connected with proteins. Hinapril and his metabolites do not get through a blood-brain barrier.

At patients with a renal failure of T1/2 of a hinaprilat increases in process of decrease in the clearance of creatinine (CC). Removal of a hinaprilat decreases also at elderly patients (65 years are more senior) and closely correlates with renal failures, however, in general distinctions in efficiency and safety of treatment of patients of elderly and younger age are not revealed.

Absorption of a hydrochlorothiazide slightly more slowly (1–2,5 h) and more stoutly (50–80%). The hydrochlorothiazide is not metabolized in a liver and removed in not changed look by kidneys. T1/2 makes from 4 to 15 h. About 61% of the dose accepted inside are removed in not changed look during 24 h. The hydrochlorothiazide gets through a placenta and into breast milk, but does not pass through a blood-brain barrier.

Indications to use:

Arterial hypertension.

Route of administration and doses:

In 1 times a day, irrespective of meal.

For the patients who are not receiving diuretics (irrespective of whether motor-therapy hinaprily was carried out earlier or not), the recommended initial dose makes 1 tablet of the drug Akkuzid® (10 mg +12,5 mg) of 1 times a day. In the subsequent if necessary the dose can be increased to 2 tablets of the drug Akkuzid® (10 mg + 12,5 mg) 1 time a day or to the maximum recommended daily dose of the drug Akkuzid® (20 mg + 25 mg) 1 time a day.
Patients with a renal failure

The initial dose of the drug Akkuzid® makes 1 tablet (10 mg +12,5 mg).

Elderly patients

Dose adjustment of the drug Akkuzid® is not required from elderly patients. The initial dose of the drug Akkuzid® makes 1 tablet (10 mg +12,5 mg).

Features of use:

Quincke's disease

At treatment APF inhibitors described cases of a Quincke's disease of the person and neck, including at 0,1% of the patients receiving hinaprit. At emergence of guttural whistle or a Quincke's disease of the face, language or a glottis the drug Akkuzid® should be cancelled immediately. The patient needs to appoint adequate treatment and to observe it before disappearance of symptoms of hypostasis. The face edema and lips usually passes without treatment. Antihistamines can be applied to reduction of symptoms. The Quincke's disease with involvement of a throat can lead to a lethal outcome. If the paraglossa, to a glottis or a throat threatens with development of obstruction of respiratory tracts, the adequate emergency treatment including hypodermic administration of solution of Epinephrinum (adrenaline) 1:1000 (0,3-0,5 ml) is necessary.

At treatment APF inhibitors described also cases of a Quincke's disease of intestines. At patients noted pain in a stomach (with/without nausea and vomiting); in certain cases without the previous Quincke's disease of the person and normal activity of S-1 of esterase. The diagnosis was established by means of a computer tomography of belly area, ultrasonic inspection or at the time of surgical intervention. Symptoms disappeared after the termination of reception of APF inhibitors. Therefore at the patients with pain in a stomach accepting APF inhibitors at establishment of the differentiated diagnosis it is necessary to consider a possibility of development of a Quincke's disease of intestines.

Patients who transferred the Quincke's disease which is not connected with reception of APF inhibitors can have risk of its development at treatment by drugs of this group.

Performing the desensibilizing therapy

At the patients receiving APF inhibitors during performing the desensibilizing therapy by poison of Hymenoptera (a wasp, a bee), permanent anaphylactoid reactions, life-threatening can develop. The temporary termination of reception of APF inhibitor promotes regression of symptoms, however they can arise again when resuming therapy by APF inhibitors.

Hemodialysis

Anaphylactoid reactions can also develop at use of APF inhibitors for patients by which carried out аферез lipoproteids of low density using a dextran of sulfate or the patients who are on a hemodialysis with use of high-flowing membranes such as poliakrilnitrilovy.

It is necessary to apply alternative hypotensive therapy or to use other membranes for a hemodialysis.

Arterial hypotension

The drug Akkuzid® can cause passing arterial hypotension, however not more often than at monotherapy by the components which are a part of drug. Symptomatic arterial hypotension seldom meets at treatment hinaprily patients uncomplicated arterial hypertension, however it can develop as a result of therapy by APF inhibitors at patients with reduced OTsK, for example, after the previous therapy with diuretics, at observance of a diet with restriction of table salt or when carrying out a hemodialysis. In case of symptomatic arterial hypotension, the patient should accept horizontal position and to carry out to it intravenous infusion using 0,9% of solution of sodium of chloride. Passing arterial hypotension is not a contraindication to further use of the drug Akkuzid®, however in similar cases it is reasonable to lower its dose.

Chronic heart failure

At patients with chronic heart failure with and/or without renal failure, therapy by APF inhibitor concerning arterial hypertension can lead to excessive decrease in the ABP which can be followed by an oliguria, an azotemia and, in rare instances, an acute renal failure and even a lethal outcome. Treatment of such patients with the drug Akkuzid® should be begun under careful medical control and observation within the first 2 weeks of therapy and at increase in a dose of drug.

Agranulocytosis

In rare instances therapy by APF inhibitors can be followed by development of an agranulocytosis and suppression of function of marrow in patients with uncomplicated arterial hypertension, but, more often, at patients with renal failures, especially with diseases of connecting fabric. In these cases it is necessary to control number of leukocytes in blood.

At emergence of any symptoms of an infection (for example, a pharyngalgia, fever) patients should see a doctor as they can be manifestation of a neutropenia immediately.

System lupus erythematosus

Thiazide diuretics can sometimes cause an aggravation of a current of a system lupus erythematosus.

Function of kidneys

The drug Akkuzid® is not recommended to be used at patients with heavy renal failures (KK less than 30 ml/min.) since thiazide diuretics promote progressing of an azotemia and have cumulative effect at prolonged use at such patients. Choice drugs at this group of the patients receiving therapy hinaprily are "loopback" diuretics. For this reason it is not necessary to apply the fixed combination a hydrochlorothiazide / хинаприл at patients with a heavy renal failure (see the section "Contraindications").

T1/2 of a hinaprilat increases at decrease in KK. The patient with KK hinaprit less than 60 ml/min., but more than 30 ml/min. it is necessary to appoint in lower initial dose. At such patients the dose of the drug Akkuzid® should be increased taking into account a clinical condition of the patient, at regular control of function of kidneys though in clinical trials further deterioration in function of kidneys at treatment was not noted by the drug Akkuzid®.

At patients with arterial hypertension without strong indications of initial disturbance of vessels of kidneys at use of a hinapril, especially in combination with diuretic, increase in concentration of an urea nitrogen in blood and creatinine in blood serum which usually was poorly expressed and passing is noted. Similar changes are most probable at patients with initial renal failures. In such cases the drug Akkuzid® dose decline can be required. At all patients with arterial hypertension it is necessary to control function of kidneys.

Influence system renin-angiotensin-aldosteronovoy (SRAA)

At some patients suppression of activity of RAAS can lead to a renal failure. At patients with heavy chronic heart failure function of kidneys depends on activity of RAAS therefore APF inhibitors, including hinaprit treatment, can lead to an oliguria and/or the progressing azotemia, and in rare instances, to an acute renal failure and/or a lethal outcome.

Renal artery stenosis

In clinical trials at patients with arterial hypertension with a bilateral stenosis of renal arteries or a stenosis of an artery of the only kidney, at treatment APF inhibitors in certain cases observed increase in concentration of an urea nitrogen and creatinine in blood serum. These changes are practically always reversible and took place after cancellation of APF inhibitor and/or diuretic. In similar cases within the first several weeks of treatment by the drug Akkuzid® control of function of kidneys is necessary.

Abnormal liver function

The drug Akkuzid® should be used with care at patients with abnormal liver functions or the progressing liver disease as small disturbances of water and electrolytic balance of blood can cause development of a "hepatic" coma.

Water and electrolytic balance of blood

For the purpose of identification of possible disturbances of water and electrolytic balance of blood it is regularly necessary to control the content of electrolytes in blood serum. At the patients receiving monotherapy hinaprily, as well as other APF inhibitors, the content of potassium can increase.

Blood serum potassium

The hyperpotassemia (> 5,8 mmol/l) was noted approximately at 2% of the patients accepting hinaprit, but in most cases this deviation was single and passed in the course of further therapy. Risk factors of development of a hyperpotassemia are: renal failures, a diabetes mellitus and a concomitant use of kaliysberegayushchy diuretics, drugs of potassium and/or the substitutes of salt containing potassium. The concomitant use of kaliysberegayushchy diuretics with the drug Akkuzid® which part thiazide diuretic is is not recommended. Treatment by thiazide diuretics on the contrary is followed by a hypopotassemia, a hyponatremia and a gipokhloremichesky alkalosis. These disturbances are sometimes shown by the following symptoms: dryness of a mucous membrane of an oral cavity, thirst, weakness, slackness, drowsiness, concern, muscular weakness, muscular pain or spasm, decrease in the ABP, oliguria, tachycardia, nausea, confusion of consciousness, spasms and vomiting.

The hypopotassemia can strengthen toxic effect of cardiac glycosides also. The risk of a hypopotassemia is increased at cirrhosis, an artificial diuresis, inadequate use of the drugs improving metabolism of a myocardium, the accompanying therapy by glucocorticosteroids or corticotropin (AKTG). At most of patients it is necessary to expect an equilibration of opposite effects of a hinapril and a hydrochlorothiazide concerning the content of potassium in blood serum.

In some cases the effect of one component of the drug Akkuzid® can prevail over another. Prior to the beginning of and during treatment by the drug Akkuzid® it is necessary to control periodically the content of electrolytes for the purpose of identification of possible disturbances of water and electrolytic balance.

The deficit of chlorides connected with therapy by thiazide diuretic is usually poorly expressed and only in exceptional cases demands the corresponding treatment (for example, at diseases of a liver and/or kidneys). 

Hyponatremia

The hyponatremia can develop in hot weather at patients with peripheral hypostases. Liquid use restriction, but not increase in the use of table salt is rather shown to such patients, except for cases when the hyponatremia threatens life. At a hyponatremia adequate replacement therapy is necessary.

Hypocalcemia

Thiazide diuretics reduce calcium removal by kidneys.

Epithelial bodies

In rare instances at the patients receiving long therapy by thiazide diuretics the changes from epithelial bodies which were followed by a hypercalcemia and a hypophosphatemia developed. More serious complications of a hyperparathyreosis (a nephrolithiasis, a resorption of a bone tissue and a round ulcer) are not described. Before carrying out a research of function of epithelial bodies thiazide diuretics need to be cancelled.

Magnesium

Thiazide diuretics increase magnesium removal by kidneys and can cause a hypomagnesiemia.

Glucose

Thiazide diuretics can reduce tolerance to glucose and increase serumal concentration of cholesterol, triglycerides and uric acid. These changes are usually poorly expressed, however at patients of risk group thiazide diuretics can provoke an aggravation of a course of gout or a diabetes mellitus.

Therapy by APF inhibitors can be followed by development of a hypoglycemia in the patients with a diabetes mellitus receiving insulin or hypoglycemic means for intake. At treatment of patients with a diabetes mellitus more careful observation and dose adjustment of hypoglycemic means can be required.

Cough

At treatment by APF inhibitors, including hinaprit, noted development of cough. In a typical case it is unproductive, resistant and passes after the therapy termination. At differential diagnosis of cough it is necessary to consider its possible communication using APF inhibitors.

Surgical intervention

At patients to whom surgical intervention or the general anesthesia is carried out APF inhibitors should be applied with care as they block the formation of angiotensin II caused by compensatory secretion of a renin. It can lead to arterial hypotension which is eliminated by increase in OTsK. In case of surgical intervention the patient has to warn the anesthesiologist, that he accepts APF inhibitor.

OTSK

Patients need to be warned that insufficient consumption of liquid, the increased sweating can lead to excessive decrease in the ABP due to decrease in OTsK. Other reasons of decrease in OTsK, such as vomiting or diarrhea, can also lead to sharp falling of the ABP.

Influence on ability to manage motor transport and other mechanisms

It is necessary to be careful at control of vehicles or performance of other work requiring special attention, especially in an initiation of treatment the drug Akkuzid®.

Side effects:

Than at 1,0% of the patients receiving hinaprit the undesirable phenomena which were found more in combination with a hydrochlorothiazide,  included the following: a headache (6,7%), dizziness (4,8%), cough (3,2%), unproductive, persistent cough which passed after the therapy termination; increased fatigue (2,9%).

In general, the undesirable phenomena were poorly expressed and passing, did not depend on age, sex, race and duration of therapy.

Laboratory indicators: increase (more than by 1,25 times in comparison with the upper bound of norm) concentration of creatinine and an urea nitrogen in blood respectively at 3% and 4% of the patients receiving was hinaprit also by a hydrochlorothiazide.

Hinaprit the undesirable phenomena which were found at 0,5-1,0% of the patients receiving in combination with a hydrochlorothiazide,  included the following:

From system of a hemopoiesis: hemolitic anemia, thrombocytopenia, leukopenia, agranulocytosis. 

From a nervous system: hyperexcitability, adynamy, paresthesias, depression, dizziness, drowsiness.

From cardiovascular system: a heart consciousness, tachycardia, the expressed decrease in the ABP, orthostatic hypotension, a syncope, disturbances of a cordial rhythm, a myocardial infarction, an ischemic stroke, peripheral hypostases (including generalized).

From respiratory system: short wind, sinusitis, синкопэ.

From the alimentary system: dryness of a mucous membrane of an oral cavity and throat, nausea, lock or diarrhea, meteorism, pancreatitis, hepatitis, Quincke's intestinal disease.

Allergic reactions: skin rash, an itch, a Quincke's disease, a photosensitization, a multiformny exudative erythema, exfoliative dermatitis, a pemphigus, Stephens-Johnson's syndrome, anaphylactic reactions, the increased sweating.

From skeletal and muscular and connecting fabric: joint pain

From urinogenital system: infections of uric ways, renal failures, decrease in a potentiality.

From an organ of sight: vision disorder.

Others: alopecia.

Interaction with other medicines:

The tetracycline and other drugs interacting with magnesium

At simultaneous use of the drug Akkuzid® and tetracycline absorption of the last decreases approximately by 28-37% because of existence as a part of the carbonate magnesium drug Akkuzid® as a filler. It is necessary to take into account this interaction at the simultaneous use of the drug Akkuzid® and tetracycline or other drugs capable to interact with magnesium.

Lithium

Lithium usually should not be applied in combination with diuretics as the last reduce renal clearance of lithium and increase risk of development of undesirable effects. At the patients accepting drugs of lithium and APF inhibitors increase in serumal concentration of lithium and symptoms of lithium intoxication is noted. These changes connect with loss of sodium under the influence of APF inhibitors. At drug Akkuzid® use the risk of intoxication can be increased by lithium. At the same time it is necessary to use these drugs with care.

At use with propranolol, digoxin and Cimetidinum of signs of clinically significant pharmacokinetic interaction it is not revealed.

The anticoagulating effect of one dose of warfarin (estimated on a prothrombin time) significantly did not change at simultaneous use about hinaprily 2 once a day.

Ethanol, barbiturates or narcotic analgetics

At simultaneous use with the drug Akkuzid® strengthening of risk of orthostatic hypotension is possible (thiazide diuretic - a hydrochlorothiazide is a part of drug).

Hypoglycemic means (hypoglycemic means for intake and insulin): dose adjustment of hypoglycemic means can be required.

Other antihypertensives

The thiazide diuretic which is a part of the drug Akkuzid® can strengthen action of other antihypertensives, especially ganglioblokator or beta adrenoblockers. Due to the maintenance of a hydrochlorothiazide hypotensive effect of the drug Akkuzid® can amplify after a sympathectomy.

Glucocorticosteroids, corticotropin (AKTG)

strengthening of loss of electrolytes, especially potassium.

Pressor amines (for example, Norepinephrinum):

decrease in therapeutic effect of pressor amines is possible (the clinical importance is insignificant)

Not depolarizing muscle relaxants (for example, Tubocurarini chloridum):

possible strengthening of action of muscle relaxants.

Non-steroidal anti-inflammatory drugs (NPVP)

Can cause easing of diuretic, natriuretic and hypotensive effect of "loopback", kaliysberegayushchy and thiazide diuretics in some sick NPVP. In this regard at simultaneous use of these drugs with the drug Akkuzid® patients have to be under observation for the purpose of assessment of efficiency of the carried-out therapy.

The drugs capable to cause a hyperpotassemia:

Hinapril – the APF inhibitor reducing concentration of Aldosteronum that in turn can lead to a hyperpotassemia. In this regard, at treatment by the drug Akkuzid®, the drugs of potassium and substitutes of salt containing potassium should be applied with care, controlling the content of potassium in blood serum. As diuretic is a part of the drug Akkuzid®, addition of kaliysberegayushchy diuretic is not recommended.

Ion-exchange resins:

Absorption of a hydrochlorothiazide decreases in the presence of Colestyraminum and a kolestipol. At single use these drugs connect a hydrochlorothiazide and reduce its absorption in digestive tract by 85 and 43%, respectively.

Contraindications:

Hypersensitivity to active agents, other auxiliary components of drug, to derivatives of sulfonamides.

Quincke's disease in the anamnesis as a result of the previous therapy by APF inhibitors.

Idiopathic and hereditary Quincke's edema.

Anury.

Heavy liver failure.

Addison's disease.

Refractory hypopotassemia, hypercalcemia and hyponatremia.

The diabetes mellitus which is (difficult controlled).

Age up to 18 years (efficiency and safety are not established).

Heavy renal failure (clearance of creatinine (CC) less than 30 ml/min.).

With care

At the patients who were earlier accepting diuretics and keeping to a diet with restriction of table salt or being on a hemodialysis; heavy chronic heart failure at patients with or without the accompanying renal failure; the states which are followed by decrease in the volume of the circulating blood (VCB) (including vomiting and diarrhea); oppression of a marrowy hemopoiesis; aortal stenosis; cerebrovascular diseases (sharp decrease in the ABP against the background of therapy by APF inhibitors can worsen the course of these diseases); a state after transplantation of a kidney; bilateral stenosis of renal arteries or stenosis of an artery of the only kidney; serious autoimmune general diseases of connecting fabric (including system lupus erythematosus, scleroderma); abnormal liver functions or the progressing liver diseases; diabetes mellitus; extensive surgical interventions and general anesthesia, concomitant use of other antihypertensives; disturbances of water and electrolytic balance, hyperpotassemia.

Use at pregnancy and during breastfeeding

Use of the drug Akkuzid® is contraindicated during pregnancy, to women to the women of reproductive age planning pregnancy, and also, not applying reliable methods of contraception.

The women of reproductive age accepting the drug Akkuzid® have to use reliable methods of contraception.

When diagnosing pregnancy the drug Akkuzid® should be cancelled as soon as possible.

Purpose of APF inhibitors during pregnancy is followed by increase in risk of development of anomalies of a cardiovascular and nervous system of a fruit. Besides, against the background of use of APF inhibitors during pregnancy, cases of an oligoamnios, premature births, the births of children with arterial hypotension, a renal failure, including an acute renal failure, a hypoplasia of bones of a skull, a contracture of extremities, craniofacial anomalies, a hypoplasia of lungs, a delay of pre-natal development, an open arterial channel, and also cases of pre-natal death of a fruit and the death of newborns are described. Often the oligoamnios is diagnosed after the fruit was is irreversible is damaged.

Newborns who were exposed to pre-natal influence of APF inhibitors should be observed for the purpose of detection of arterial hypotension, an oliguria and a hyperpotassemia. At emergence of an oliguria it is necessary to support the ABP and perfusion of kidneys.

Tiazida get through a placenta and are found in umbilical cord blood. Not teratogenic effects of tiazid include jaundice and thrombocytopenia of a fruit and/or the newborn, the possibility of manifestation of other undesirable phenomena which are observed at mother is also allowed.

APF inhibitors, including hinaprit, in limited degree get into breast milk. Tiazida get into breast milk. Considering a possibility of development of the serious undesirable phenomena in the newborn, the drug Akkuzid® needs to be cancelled in the period of a lactation or to stop feeding by a breast.

Overdose:

There are no data on overdose of the drug Akkuzid® and special measures for its therapy.

Symptoms: the expressed decrease in the ABP, disturbance of water and electrolytic balance: a hyponatremia, a hypochloraemia, a hypopotassemia (at simultaneous use with cardiac glycosides the risk of development of arrhythmia amplifies), decrease in the volume of the circulating blood (VCB) against the background of an artificial diuresis.

Treatment: to stop administration of drug, to wash out a stomach, to accept absorbent carbon, intravenous administration of 0,9% of solution of sodium of chloride, recovery of water and electrolytic balance of blood, a symptomatic and maintenance therapy.

Storage conditions:

At a temperature not over 25 to °s.khranit in the place, unavailable to children. A period of validity - 3 years. Not to use after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Tablets, film coated 12,5 mg + 10 mg; 12,5 mg + 20 mg; 25 mg + 20 mg. 10 tablets in the blister from PAS/Al/PVC of a foil; on 3 blisters with the application instruction in a cardboard pack.