Neospastil solution 15mg/ml ampoule 2 ml No. 10

Instructions Neospastil solution 15mg/ml ampoule 2 ml No. 10

Composition

active ingredients: ketorolac tromethamine, pitofenone hydrochloride, fenpiverinium bromide.

1 ml of solution contains: ketorolac tromethamine 15 mg, pitofenone hydrochloride 5 mg, fenpiverinium bromide 0.05 mg.

Excipients: sodium chloride, propylene glycol, disodium edetate, water for injections.

Dosage form

Solution for injection.

Main physicochemical properties: transparent slightly yellowish or slightly greenish liquid.

Pharmacotherapeutic group

Antispasmodics in combination with analgesics.

ATX code A03D A02.

Pharmacological properties

Pharmacodynamics.

Neospastil® is a combination drug that belongs to the group of antispasmodics combined with analgesics. It contains three active ingredients: the non-narcotic analgesic ketorolac tromethamine, the myotropic antispasmodic pitofenone hydrochloride, and the anticholinergic fenpiverinium bromide.

Ketorolac is a nonsteroidal anti-inflammatory drug (NSAID), a cyclooxygenase (COX)-1 and COX-2 inhibitor, a pyrrolysine carboxylic acid derivative, which has a pronounced analgesic effect. The mechanism of action of ketorolac (as well as other NSAIDs) is not fully understood, but may involve inhibition of prostaglandin synthesis. The biological activity of ketorolac tromethamine is associated with the S-form. Ketorolac tromethamine does not have sedative or anxiolytic properties. It is not an opioid, therefore it does not affect opiate receptors.

The maximum analgesic effect of ketorolac is achieved within 2–3 hours. This effect is not statistically significantly different within the recommended dosage range. The greatest difference between high and low doses of ketorolac is the duration of analgesia. The analgesic dose of ketorolac also has an anti-inflammatory effect.

Fenpiverinium bromide has a moderate ganglioblocking and anticholinergic effect, suppresses the tone and motility of the smooth muscles of the stomach, intestines, biliary and urinary tracts.

Pitofenone hydrochloride has a papaverine-like effect with pronounced antispasmodic activity on smooth muscles.

The combination of the three components of the drug leads to a mutual enhancement of their pharmacodynamic action, which is manifested by pain relief, relaxation of smooth muscles, and a decrease in body temperature.

Clinical trials

A pivotal prospective multicenter randomized comparative clinical trial of the drug Neospastil® was conducted in parallel groups, KPF07-T. The aim of this study was to evaluate the efficacy and safety of the drug Neospastil® compared with ketorolac tromethamine in patients with pain syndrome after abdominal and pelvic surgery. The study randomized 424 patients. Patients with a resting pain level of 4–8 points inclusive on an 11-point numerical rating scale (NRS) on the first day of treatment were prescribed the study drugs in the form of a solution for intramuscular injection (1 ampoule three times a day every 8 hours). From day 2, patients were prescribed oral study drugs if, in particular, the level of pain during movement was 4–6 points on the CRS or 7 points, if at rest the level of pain did not exceed 6 points on the 11-point CRS. Study drugs were prescribed 1 tablet 4 times a day for 24 hours, with a subsequent transition to taking as needed. The total duration of study treatment in the KPF07-T trial did not exceed 5 days.

The superior efficacy of the drug Neospastil®, solution for injection, compared to ketorolac tromethamine in the form of a solution for injection in patients with pain syndrome after abdominal and pelvic surgery has been proven both in terms of the main efficacy indicator (primary endpoint) and in terms of additional efficacy indicators (secondary endpoints), in particular:

The proportion of study subjects who achieved a response to treatment within the first 24 hours of using the drug in the form of a solution for injection in the main group (Neospastil®) was 68.9%, and in the control group (ketorolac tromethamine) - 36.2% (p < 0.001).

The median time to a noticeable and significant reduction in pain intensity at rest from the moment of the first dose of the drug in the form of a solution for injection in the main group was 25 minutes and 55 minutes, respectively, and in the control group - 34 minutes and 64 minutes, respectively (p < 0.001).

The median area under the curve (AUC) of pain intensity according to the CNS at rest during therapy with the injectable form of the drug was statistically significantly lower in the main group (Neospastil®) - 64.38 compared to the control group (ketorolac tromethamine) - 72.5 (p < 0.001). In motion, this indicator was 77.25 and 90.13, respectively (p < 0.001).

The proportion of study subjects who achieved a response to treatment based on the patient's overall assessment of pain control within 24 hours of using the drug in the form of a solution for injection, taking into account the intake of other analgesics, was 84.0% in the main group (Neospastil®) and 16.7% in the control group (ketorolac tromethamine) (p < 0.001).

Pharmacokinetics.

Neospastil®

In healthy volunteers, after intramuscular administration of the drug Neospastil®, maximum plasma concentrations of fenpiverinium and pitofenone were reached after 0.75 hours, and ketorolac after 1.33 hours.

Table 1

AUC0–t and Cmax of ketorolac, fenpiverinium and pitofenone after a single intramuscular injection of 2 ml of the drug Neospastil® (mean ± SD)

In healthy volunteers, after intramuscular administration of Neospastil®, the half-life of ketorolac, fenpiverinium and pitofenone was 5.71 ± 0.65 h, 4.44 ± 1.60 h and 2.25 ± 2.65 h, respectively. The pharmacokinetic profiles of ketorolac, fenpiverinium and pitofenone decreased multiexponentially.

Ketorolac tromethamine

Ketorolac tromethamine is a racemic mixture of [-] S and [+] R-enantiomeric forms, with the analgesic activity being due to the S-form. Ketorolac is rapidly and completely absorbed after intramuscular administration. The mean maximum plasma concentration of 2.2 μg/ml is reached on average 50 minutes after administration of a single 30 mg dose.

Linear pharmacokinetics.

In adults, clearance of the racemate is not altered after intramuscular administration of ketorolac tromethamine in the recommended dosage range. This indicates that the pharmacokinetics of ketorolac tromethamine in adults after single or multiple intramuscular administrations are linear. At higher recommended doses, there is a proportional increase in concentrations of the free and bound racemate.

Ketorolac does not penetrate the blood-brain barrier well. Ketorolac crosses the placenta and in small amounts is excreted in breast milk. In plasma, more than 99% of ketorolac is bound to proteins over a wide range of concentrations.

Table 2

Approximate mean pharmacokinetic parameters of ketorolac after intramuscular administration (mean ± SD)

Metabolism.

Ketorolac tromethamine is extensively metabolized in the liver. The products of metabolism are hydroxylated and conjugated forms of the drug derivatives. The products of metabolism and some of the unchanged drug are excreted in the urine.

Excretion.

The main route of elimination of ketorolac and its metabolites is renal. Approximately 92% of the administered dose is determined in the urine: approximately 40% - in the form of metabolites and 60% - in the form of unchanged ketorolac. Approximately 6% of the dose is excreted in the feces. In a study with a single administration of ketorolac at a dose of 10 mg, it was demonstrated that the S-enantiomer is excreted twice as fast as the R-enantiomer, and the clearance is independent of the route of administration. This means that the ratio of plasma concentrations of the S-enantiomer/R-enantiomer after the administration of each subsequent dose decreases over time. The differences between the S- and R-forms in the human body are insignificant or absent.

The half-life of the S-enantiomer of ketorolac tromethamine is approximately 2.5 hours and the R-enantiomer is 5 hours. Other studies have reported a half-life of the racemate of 5–6 hours.

Administration of ketorolac tromethamine intravenously every 6 hours for 5 days to healthy volunteers did not demonstrate a significant difference between Cmax values on days 1 and 5. Trough levels averaged 0.29 μg/mL on day 1 and 0.55 μg/mL on day 6. Steady state was achieved after the fourth dose. Accumulation of ketorolac tromethamine in specific patient groups (elderly, pediatric, renally impaired, or hepatically impaired) has not been studied.

Pharmacokinetics in patients of certain groups.

Elderly patients.

Based only on data obtained after a single administration, the elimination half-life of the racemate ketorolac tromethamine was increased from 5 to 7 hours in elderly patients (65-78 years) compared to young healthy volunteers (24-35 years).

Children: Pharmacokinetic data on intramuscular administration of ketorolac tromethamine in children are not available.

Kidney failure.

Based on single-dose data, the elimination half-life of ketorolac tromethamine in patients with renal impairment ranges from 6 to 19 hours, depending on the severity of the impairment. There is little correlation between creatinine clearance and total clearance of ketorolac tromethamine in elderly patients and patients with renal impairment. In patients with renal disease, the AUC0–∞ of each enantiomer is increased by almost 100% compared to healthy volunteers. The volume of distribution is doubled for the S-enantiomer and increased by 1/5 for the R-enantiomer. The increase in the volume of distribution of ketorolac tromethamine indicates an increase in the unbound fraction.

Liver failure.

The values of half-life, AUC0–∞ and Cmax in 7 patients with liver disease did not differ significantly from those in healthy volunteers.

Fenpiverinium bromide.

The pharmacokinetics of fenpiverinium have not been studied separately.

Pitofenone hydrochloride.

The pharmacokinetics of pitofenone have not been studied separately.

Indication

For short-term symptomatic treatment of moderate to severe pain:

for spasms of the smooth muscles of internal organs: renal colic, spasms of the bladder and urinary tract, hepatic colic, spasms of the stomach and intestines, spastic dyskinesia of the biliary tract;

after surgical interventions and diagnostic procedures on the visceral organs of the abdominal cavity and pelvis.

Contraindication

Hypersensitivity to ketorolac, fenpiverinium, pitofenone or any other component of the drug;

active peptic ulcer, recent gastrointestinal bleeding or perforation, peptic ulcer disease or history of gastrointestinal bleeding;

bronchial asthma, rhinitis, angioedema or urticaria caused by the use of acetylsalicylic acid or other non-steroidal anti-inflammatory drugs (due to the possibility of severe anaphylactic reactions);

history of bronchial asthma;

complete or partial nasal polyps syndrome, angioedema or bronchospasm;

use as an analgesic before and during surgery, during manipulations on the coronary vessels;

use in patients who have had surgery with a high risk of hemorrhage or incomplete bleeding, and in patients receiving anticoagulants, including warfarin or heparin in low doses (2500-5000 units every 12 hours);

severe heart failure;

severe liver failure;

moderate/severe renal failure (serum creatinine concentration more than 160 μmol/l);

suspected or confirmed cerebrovascular bleeding, hemorrhagic diathesis, including blood clotting disorders, high risk of bleeding;

concomitant treatment with acetylsalicylic acid or other non-steroidal anti-inflammatory drugs (NSAIDs) (including selective cyclooxygenase-2 inhibitors), pentoxifylline, probenecid or lithium salts;

hypovolemia, dehydration with risk of renal failure due to decreased fluid volume;

labor and delivery;

prostate adenoma of II and III degree;

atony of the gallbladder and urinary bladder;

tachyarrhythmia;

collaptoid state;

closed-angle glaucoma;

gastrointestinal obstruction and megacolon;

administration of the drug epidurally or intrathecally.

Interaction with other medicinal products and other types of interactions

The interaction of Neospastil® with other drugs is due to the content of ketorolac tromethamine. Ketorolac is highly bound to blood plasma proteins (on average 99.2%). Ketorolac does not change the pharmacokinetics of other drugs through enzyme induction or inhibition.

Since ketorolac is a potent drug and its plasma levels are low, it is unlikely that it can significantly displace other drugs from plasma protein binding.

Medicines that are contraindicated for use with Neospastil®

Acetylsalicylic acid and other NSAIDs. When used with acetylsalicylic acid, the binding of ketorolac to plasma proteins is reduced, although the clearance of free ketorolac is not changed. The clinical significance of this interaction is unknown, although, as with other NSAIDs, the simultaneous use of ketorolac tromethamine and acetylsalicylic acid is contraindicated due to the potential increase in the incidence of adverse events.

Anticoagulants: Concomitant use with anticoagulants may increase bleeding. Concomitant use with anticoagulants (such as warfarin) is contraindicated.

Lithium. The simultaneous use of NSAIDs and lithium preparations is contraindicated.

Probenecid: Concomitant administration of ketorolac tromethamine and probenecid resulted in decreased clearance of ketorolac, significantly increased plasma levels, and prolonged elimination half-life. Therefore, concomitant use of ketorolac tromethamine and probenecid is contraindicated.

Mifepristone: NSAIDs should not be used for 8–12 days after mifepristone administration, as they may weaken the effects of mifepristone.

Pentoxifylline: Concomitant use of ketorolac tromethamine and pentoxifylline increases the risk of bleeding.

Medicines that should be used with caution in combination with Neospastil®

Corticosteroids: As with all NSAIDs, caution should be exercised when corticosteroids are administered concomitantly due to the increased risk of gastrointestinal bleeding.

Selective serotonin reuptake inhibitors (SSRIs). There is an increased risk of gastrointestinal bleeding with concomitant use of SSRIs and NSAIDs. Caution should be exercised when using them concomitantly.

Methotrexate: Since NSAIDs may reduce the clearance of methotrexate, the toxicity of the latter may be increased.

Diuretics: Ketorolac may reduce the natriuretic effect of furosemide and thiazides in some patients. During concomitant therapy with NSAIDs, the patient should be closely monitored for signs of renal failure and to ensure the effectiveness of the diuretic.

Antihypertensives. When used simultaneously with ketorolac, the effect of these drugs is weakened. Ketorolac and other NSAIDs may reduce the antihypertensive effect of beta-blockers, angiotensin-converting enzyme (ACE) inhibitors and angiotensin-II receptor antagonists, and may increase the risk of renal dysfunction; this is especially true in patients with reduced blood volume or elderly patients. Therefore, this combination should be prescribed with caution, especially in elderly patients. Patients should be closely monitored, and renal function should be periodically monitored after starting and stopping concomitant therapy, especially when using diuretics and ACE inhibitors.

Cardiac glycosides: NSAIDs may worsen heart failure, reduce glomerular filtration rate, and increase plasma levels of cardiac glycosides when used concomitantly with the latter.

Thrombolytic agents. Concomitant use with NSAIDs increases the risk of bleeding.

Cyclosporine: As with all NSAIDs, caution should be exercised when co-administering cyclosporine due to the increased risk of nephrotoxicity.

Tacrolimus: NSAIDs may increase the risk of nephrotoxicity.

Opioid analgesics. The effect of opioid analgesics is enhanced, which allows for a reduction in the dose of the latter for pain relief.

Quinolones: Patients taking quinolines may be at increased risk of seizures.

Zidovudine: Concomitant use of NSAIDs with zidovudine increases the risk of hematological toxicity. There is an increased risk of hemarthrosis and hematoma in HIV-infected patients with hemophilia treated concomitantly with zidovudine and ibuprofen.

Anticonvulsants: Isolated cases of seizures have been reported during concomitant use of ketorolac tromethamine and anticonvulsants (phenytoin, carbamazepine).

Psychotropic drugs: Hallucinations have been reported with the concomitant use of ketorolac and psychotropic drugs (fluoxetine, thiotexene, alprazolam).

Non-depolarizing muscle relaxants: No studies have been conducted on the concomitant use of ketorolac tromethamine and muscle relaxants. Cases of a possible interaction between ketorolac and non-depolarizing muscle relaxants resulting in apnea have been reported.

Antidiabetic agents: NSAIDs may enhance the effects of sulfonylureas.

Preparations containing garlic, onion, and ginkgo biloba may enhance the effect of ketorolac and increase the risk of hemorrhagic complications.

When using Neospastil® with quinine preparations, the anticholinergic effect may be enhanced.

Application features

It is recommended to use in a hospital setting.

The likelihood of side effects can be minimized by using the lowest effective dose for the shortest time necessary to control symptoms.

The simultaneous use of the drug Neospastil® and NSAIDs, as well as selective cyclooxygenase-2 inhibitors, is contraindicated (see the section "Contraindications").

When treating patients with cardiac, renal or hepatic insufficiency who are taking diuretics, or patients with hypovolemia after surgery, careful monitoring of diuresis and renal function is necessary.

Use in elderly patients

In elderly patients (over 65 years of age), the use of NSAIDs is more likely to cause undesirable side effects, especially bleeding and perforation of the gastrointestinal tract, including fatal outcomes (see section "Method of administration and dosage").

This increased risk associated with age is common to all NSAIDs. Compared with younger patients, these patients have a longer plasma half-life and a lower plasma clearance. Therefore, elderly patients are not recommended to be prescribed Neospastil® in a daily dose exceeding 60 mg in terms of ketorolac tromethamine (see section "Method of administration and dosage").

Gastrointestinal disorders. The active substance of Neospastil®, ketorolac tromethamine, can cause severe gastrointestinal adverse reactions. These adverse reactions can occur in patients taking ketorolac tromethamine at any time after or without warning symptoms and can be fatal. The risk of clinically significant gastrointestinal bleeding is dose-dependent. However, adverse reactions can occur even with short-term therapy. In addition to a history of peptic ulcer disease, predisposing factors include concomitant use of oral corticosteroids, anticoagulants, long-term NSAID therapy, smoking, alcohol consumption, advanced age, and poor general health. Most spontaneous reports of adverse events from the digestive tract concerned elderly or debilitated patients, therefore, special attention is required when treating such patients, and if adverse reactions are suspected, the drug should be discontinued. Patients at risk should be prescribed an alternative type of therapy that does not include NSAIDs.

NSAIDs should be used with caution in patients with a history of Crohn's disease and ulcerative colitis due to the possibility of worsening of the disease.

The drug should be used with caution in patients with obstructive diseases of the gastrointestinal tract (achalasia, pyloroduodenal stenosis). Repeated use of the drug Neospastil® in these cases may cause a delay in the elimination of gastrointestinal contents. The use of Neospastil® in patients with gastroesophageal reflux disease, intestinal atony, inflammatory bowel diseases, including nonspecific ulcerative colitis and Crohn's disease, requires special caution and medical supervision.

The use of NSAIDs, including ketorolac, may be associated with an increased risk of gastrointestinal anastomotic leakage. Close medical supervision and caution are recommended when using ketorolac after gastrointestinal surgery.

Hematological effects. Concomitant use of ketorolac tromethamine in patients receiving anticoagulant therapy may increase the risk of bleeding. Although detailed studies of the concomitant use of ketorolac and heparin in prophylactic low doses (2500–5000 IU every 12 hours) have not been conducted, an increased risk of bleeding with this regimen cannot be excluded. Patients already receiving anticoagulants or who require low-dose heparin should not receive ketorolac tromethamine. Patients receiving ketorolac tromethamine should be closely monitored in patients receiving other agents that adversely affect hemostasis. Ketorolac inhibits platelet aggregation and prolongs bleeding time. In patients with normal hemostasis, bleeding time is increased but does not exceed the normal range of 2 to 11 minutes. Unlike the prolonged effect of acetylsalicylic acid, platelet function returns to normal within 24–48 hours after ketorolac discontinuation. Ketorolac tromethamine is contraindicated in patients undergoing surgery with a high risk of bleeding or incomplete hemostasis. Ketorolac tromethamine is not an anesthetic and does not have sedative or anxiolytic properties.

Use in patients with renal impairment (see Contraindications). Like other NSAIDs, ketorolac inhibits prostaglandin synthesis and may be toxic to the kidneys, and should be used with caution in patients with renal impairment or a history of renal disease. Patients at risk include patients with renal impairment, hypovolemia, heart failure, hepatic impairment, patients taking diuretics, and the elderly.

Patients with less severe renal impairment should receive lower doses of ketorolac (not more than 60 mg/day intramuscularly). The renal status of such patients should be closely monitored. Patients should be well hydrated before starting treatment with the drug. In patients undergoing hemodialysis, ketorolac clearance was reduced to approximately half of normal, and the terminal half-life was increased by almost threefold.

Due to the fact that both old age (> 65 years) and impaired renal function require a reduction in the daily dose of the drug, and also due to the lack of clinical data on the pharmacokinetics of the drug in this population, the drug should be used in elderly patients with impaired renal function only after a careful assessment of the benefits and risks associated with such therapy.

Effects on the cardiovascular system and cerebral vessels. Patients with arterial hypertension and/or a history of mild to moderate heart failure should be closely monitored. The use of Neospastil® in patients with heart disease (arrhythmias, ischemic heart disease, congestive heart failure) requires special caution and monitoring by a physician.

To minimize the potential risk of adverse cardiovascular events in patients taking NSAIDs, the lowest effective dose should be used for the shortest possible duration. Ketorolac tromethamine should be used in patients with uncontrolled hypertension, congestive heart failure, established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease only after careful consideration of the benefits and risks. Ketorolac should also be considered before initiating long-term treatment in patients at risk for cardiovascular disease (e.g., patients with hypertension, hyperlipidemia, diabetes mellitus, and smokers).

Clinical trials and epidemiological data suggest that the use of some NSAIDs, particularly at high doses and over long periods, may be associated with a small increased risk of arterial thromboembolic events such as myocardial infarction or stroke. Such a risk cannot be excluded for ketorolac.

Use in Patients with Hepatic Impairment. Ketorolac tromethamine should be used with caution in patients with impaired hepatic function or a history of liver disease. Significant elevations (greater than three times the upper limit of normal) in serum alanine aminotransferase and aspartate aminotransferase have been observed in less than 1% of patients. In addition, there have been isolated reports of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, hepatic necrosis, and hepatic failure, some of which have been fatal. Ketorolac should be discontinued if clinical signs of liver disease or systemic manifestations (e.g., eosinophilia, rash) develop.

Respiratory system: The patient's condition should be monitored due to the possibility of bronchospasm.

Systemic lupus erythematosus and mixed connective tissue diseases: Patients with systemic lupus erythematosus and various mixed connective tissue diseases are at increased risk of developing aseptic meningitis.

Dermatological disorders: Serious skin reactions such as exfoliative dermatitis, Stevens-Johnson syndrome, and Lyell's syndrome have been reported. The risk of these reactions is highest early in treatment. Patients should discontinue treatment at the first appearance of rash, mucosal lesions, or other signs of hypersensitivity.

Fluid retention and edema: Fluid retention and edema have been reported with ketorolac, and therefore ketorolac should be used with caution in patients with cardiac decompensation, hypertension, or similar conditions.

Prostatic hyperplasia. Use with caution in prostatic hyperplasia.

Nervous system and organs of vision. The use of Neospastil® in patients with glaucoma or myasthenia gravis requires special caution and monitoring by a doctor. With prolonged use of the drug, its anticholinergic effect may lead to dizziness or accommodation disorders.

Effects on Fertility: Ketorolac tromethamine should be discontinued in women who are unable to conceive and are undergoing evaluation for this condition. Women with reduced fertility should avoid the drug.

Excipients: When using the drug at the maximum daily dose, the highest dose of propylene glycol that the patient can receive does not exceed 50 mg/kg/day.

Use during pregnancy or breastfeeding

Due to the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system, ketorolac-containing medicinal products are contraindicated during pregnancy (especially in the third trimester). Ketorolac tromethamine is contraindicated during pregnancy, labor and delivery.

Do not use during breastfeeding due to the possible negative effects of prostaglandin synthesis inhibitors on infants.

Ability to influence reaction speed when driving vehicles or other mechanisms

The drug may reduce the psychophysical capabilities of patients and adversely affect activities that require increased attention, coordination of movements and quick reactions (for example, driving a car, working with mechanisms, working at heights). Some patients may experience dizziness, drowsiness, visual disturbances, headache, vertigo, insomnia or depression when using drugs containing ketorolac tromethamine. If a patient experiences these or other similar side effects, he should not drive or operate other mechanisms.

Method of administration and doses

It is recommended to use in a hospital setting.

After intramuscular administration, the analgesic effect is observed after approximately 30 minutes, and maximum analgesia occurs after 1–2 hours. In general, the average duration of analgesia is 8–12 hours. The dose should be adjusted depending on the severity of the pain and the patient's response to treatment. The likelihood of side effects can be minimized by using the lowest effective dose for the shortest time necessary to control symptoms. The drug is contraindicated for epidural or intraspinal administration.

Before injection, it is recommended to warm the ampoule with the drug to body temperature.

Adults

For spasms of the smooth muscles of internal organs.

The recommended dose of Neospastil® is 1–2 ml (15–30 mg in terms of ketorolac tromethamine) every 8 hours. The minimum effective dose should be prescribed. The maximum duration of treatment should not exceed 2 days.

For the relief of visceral pain after surgical interventions and diagnostic procedures on the visceral organs of the abdominal cavity and pelvis

The recommended initial dose of Neospastil® is 1 ml (15 mg equivalent to ketorolac tromethamine) followed by 1–2 ml (15–30 mg equivalent to ketorolac tromethamine) every 8–12 hours as needed. The minimum effective dose should be administered. Maximum duration of treatment