Moviflex Dex solution for injection 50 mg/2 ml ampoules 2 ml No. 6

Instructions for Moviflex Dex solution for injection 50 mg/2 ml ampoules 2 ml No. 6

Composition

active ingredient: dexketoprofen trometamol;

1 ampoule of 2 ml of solution for injection contains 73.8 mg of dexketoprofen trometamol, equivalent to 50 mg of dexketoprofen (1 ml of solution for injection contains 36.9 mg of dexketoprofen trometamol, equivalent to 25 mg of dexketoprofen);

Excipients: ethanol 96%, sodium chloride, sodium hydroxide, water for injections.

Dosage form

Solution for injection.

Main physicochemical properties: almost transparent, colorless solution.

Pharmacotherapeutic group

Nonsteroidal anti-inflammatory and antirheumatic drugs. Propionic acid derivatives. Dexketoprofen. ATX code M01A E17.

Pharmacological properties

Dexketoprofen trometamol is the tromethamine salt of (S)-(+)-2-(3-benzoylphenyl)propionic acid, which has analgesic, anti-inflammatory and antipyretic effects and belongs to the class of non-steroidal anti-inflammatory drugs (NSAIDs).

Mechanism of action. The mechanism of action of NSAIDs is based on a decrease in prostaglandin synthesis by inhibiting cyclooxygenase activity. In particular, the conversion of arachidonic acid into cyclic endoperoxides PGG2 and PGH2 is inhibited, from which prostaglandins PGE1, PGE2, PGF2a, PGD2 are formed, as well as prostacyclin PGI2 and thromboxanes ThA2 and ThB2. In addition, inhibition of prostaglandin synthesis may affect other inflammatory mediators, such as kinins, which may also indirectly affect the main effect of the drug.

Pharmacodynamics

Studies have shown an inhibitory effect of dexketoprofen trometamol on the activity of cyclooxygenase-1 and cyclooxygenase-2 (in laboratory animals and humans).

Clinical efficacy and safety

Clinical studies in various types of pain have demonstrated that dexketoprofen trometamol has a pronounced analgesic effect. The analgesic effect of dexketoprofen trometamol when administered intramuscularly and intravenously to patients with moderate to severe pain has been studied in various types of surgical pain (orthopedic and gynecological operations, abdominal operations), as well as in musculoskeletal pain (acute low back pain) and renal colic. In the studies conducted, the analgesic effect of the drug began quickly and reached a maximum within the first 45 minutes. The duration of the analgesic effect after the use of 50 mg of dexketoprofen trometamol is usually 8 hours.

Clinical trials in the management of postoperative pain have demonstrated that the use of dexketoprofen trometamol in combination with opiate analgesics significantly reduces the use of opioids. In these trials, patients receiving morphine via a patient-controlled analgesia device required significantly less morphine (30–45%) than patients receiving placebo.

Pharmacokinetics

Absorption

After intramuscular administration of dexketoprofen trometamol, its maximum concentration is reached after approximately 20 minutes (10–45 minutes). When 25–50 mg of the drug is administered, the area under the concentration-time curve (AUC) is proportional to the administered dose for both intramuscular and intravenous routes of administration.

Distribution

Similar to other drugs with a high degree of binding to plasma proteins (99%), the volume of distribution of dexketoprofen is on average 0.25 l/kg. The half-life is approximately 0.35 hours, and the half-life is 1–2.7 hours.

Pharmacokinetic studies of multiple administration of the drug have shown that AUC and Cmax (mean maximum value) after the last intramuscular and intravenous administration do not differ from those after a single administration, indicating the absence of drug accumulation.

Biotransformation and excretion

After administration of dexketoprofen trometamol, only the S-(+) enantiomer is detected in the urine, indicating that there is no transformation of the drug into the R-(-) enantiomer in humans. The metabolism of dexketoprofen occurs mainly by conjugation with glucuronic acid and subsequent renal excretion.

Elderly patients

In healthy elderly subjects (aged 65 years and over), exposure was significantly higher than in young volunteers after single and multiple oral doses (up to 55%), while there was no statistically significant difference in peak concentrations and time to peak concentration. The mean half-life was increased (up to 48%) and the estimated total clearance was reduced.

Preclinical safety data

Studies of safety pharmacology, genotoxicity and immunopharmacology revealed no special hazard for humans. In chronic toxicity studies in mice and monkeys, a NOAEL of 3 mg/kg/day (no observed adverse effect level) was obtained.

Like all NSAIDs, dexketoprofen trometamol may cause changes in fetal survival in the embryo-fetal period in animal models, both indirectly, through gastrointestinal toxicity in pregnant women, and through direct effects on fetal development.

Indication

Symptomatic treatment of acute pain of moderate to severe intensity in cases where oral administration of the drug is inappropriate, for example, postoperative pain, renal colic and low back pain.

Contraindication

- 3rd trimester of pregnancy and breastfeeding period.

- Hypersensitivity to dexketoprofen, any other NSAID or to the excipients of the drug.

- NSAIDs are contraindicated in patients with a history of hypersensitivity reactions (e.g. bronchospasm, acute rhinitis or development of nasal polyps, angioedema or urticaria) following the use of ibuprofen, acetylsalicylic acid or other NSAIDs.

- Photoallergic or phototoxic reactions are known during treatment with ketoprofen or fibrates.

- Active phase or history of peptic ulcer disease, gastrointestinal bleeding or perforation.

- History of gastrointestinal bleeding or perforation related to previous NSAID therapy.

- Gastrointestinal bleeding, other bleeding in the active phase or increased bleeding.

- Hemorrhagic diathesis and other blood clotting disorders.

- Chronic dyspepsia.

- Crohn's disease or nonspecific ulcerative colitis.

- Severe dehydration (due to vomiting, diarrhea, or insufficient fluid intake).

- Severe heart failure.

- Moderate or severe renal impairment (creatinine clearance ≤ 59 ml/min).

- Severe liver dysfunction (10–15 points on the Child–Pugh scale).

Due to the ethanol content, the drug is contraindicated for neuraxial (intrathecal or epidural) administration.

Interaction with other medicinal products and other types of interactions

The following drug interactions are generally typical of NSAIDs.

Concomitant use with the following medications is not recommended:

− Other NSAIDs, including selective cyclooxygenase-2 inhibitors, salicylates in high doses (≥ 3 g/day): the use of multiple NSAIDs simultaneously increases the risk of gastrointestinal ulcers and bleeding due to synergistic effects.

− Anticoagulants: NSAIDs enhance the effect of anticoagulants, such as warfarin, due to the high degree of binding of dexketoprofen to blood plasma proteins, as well as inhibition of platelet function and damage to the gastric and duodenal mucosa. If concomitant use is necessary, it should be carried out under close medical supervision and appropriate laboratory parameters.

− Heparins: increased risk of bleeding (due to inhibition of platelet function and damage to the gastric and duodenal mucosa). If concomitant use is necessary, it should be carried out under medical supervision and with careful monitoring of relevant laboratory parameters.

− Corticosteroids: increased risk of peptic ulcers and gastrointestinal bleeding.

− Lithium preparations: (reported for several NSAIDs) NSAIDs increase the level of lithium in the blood, which can lead to intoxication, by reducing its excretion by the kidneys. Therefore, when starting dexketoprofen, when adjusting the dose or when discontinuing the drug, it is necessary to monitor the level of lithium in the blood.

− Methotrexate when used in high doses (at least 15 mg/week): due to the decrease in renal clearance of methotrexate against the background of the use of NSAIDs, its negative effect on the blood system is generally increased.

− Hydantoin derivatives and sulfonamides: possible increase in the toxicity of these substances.

The simultaneous use of such agents with NSAIDs requires caution:

− Diuretics, ACE inhibitors, aminoglycoside antibiotics and angiotensin II receptor antagonists. Dexketoprofen reduces the effectiveness of diuretics and other antihypertensive agents. In some patients with impaired renal function (e.g., in cases of dehydration or in the elderly), the use of NSAIDs simultaneously with ACE inhibitors, angiotensin II receptor antagonists or aminoglycoside antibiotics may worsen renal function, which is usually reversible. When using dexketoprofen simultaneously with any diuretic, it is necessary to ensure that the patient is not dehydrated, and at the beginning of treatment it is necessary to monitor renal function.

− Methotrexate when used in low doses (less than 15 mg/week): due to the decrease in renal clearance of methotrexate against the background of the use of NSAIDs, its negative effect on the blood system is increased. If it is necessary to use such a combination, weekly monitoring of the blood picture is necessary, especially in the presence of even a slight decrease in renal function, as well as in elderly patients.

− Pentoxifylline: there is a risk of bleeding. It is necessary to increase monitoring and check the bleeding time more frequently.

− Zidovudine: there is a risk of increased toxicity to red blood cells due to effects on reticulocytes, leading to severe anemia after the first week of NSAID use. A blood test with a reticulocyte count should be performed within 1–2 weeks of starting NSAID use.

− Sulfonylureas: NSAIDs may enhance the hypoglycemic effect of sulfonylureas by displacing them from blood protein binding.

− Beta-blockers: NSAIDs can reduce their antihypertensive effect by inhibiting prostaglandin synthesis.

− Cyclosporine and tacrolimus: possible increase in nephrotoxicity due to the effect of NSAIDs on renal prostaglandins. Renal function should be monitored during combination therapy.

− Thrombolytic agents: increased risk of bleeding.

− Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding.

− Probenecid: an increase in dexketoprofen plasma concentration is possible, which is probably due to inhibition of its renal tubular secretion and glucuronidation and requires correction of the dexketoprofen dose.

− Cardiac glycosides: NSAIDs can increase the concentration of glycosides in the blood plasma.

− Mifepristone: There is a theoretical risk that the efficacy of mifepristone may be altered by prostaglandin synthetase inhibitors. Limited data suggest that co-administration of NSAIDs on the same day as a prostaglandin does not adversely affect the efficacy of mifepristone or prostaglandin in cervical ripening or contractility, nor does it reduce the clinical efficacy of medical abortion.

− Quinoline antibiotics: animal studies have shown that the use of quinolone derivatives in high doses in combination with NSAIDs increases the risk of seizures.

− Tenofovir: when used concomitantly with NSAIDs, the concentration of urea nitrogen and creatinine in the blood plasma may increase, therefore, renal function should be monitored to assess the possible effect of the concomitant use of these drugs.

− Deferasirox: Concomitant use with NSAIDs may increase the risk of gastrointestinal toxicity. Careful patient monitoring is required when this medicinal product is used concomitantly with deferasirox.

− Pemetrexed: Pemetrexed elimination may be reduced when co-administered with NSAIDs, therefore special caution should be exercised when using NSAIDs at high doses. In patients with mild to moderate renal impairment (creatinine clearance 45 to 79 ml/min), the concomitant use of pemetrexed and NSAIDs should be avoided for two days before and two days after pemetrexed administration.

Application features

Use with caution in patients with a history of allergic conditions. Avoid use of the drug in combination with other NSAIDs, including selective cyclooxygenase-2 inhibitors. Adverse reactions can be minimized by using the lowest effective dose for the shortest time necessary to improve the condition.

Gastrointestinal safety

Gastrointestinal bleeding, ulceration or perforation, in some cases fatal, have been reported with all NSAIDs at various stages of treatment, regardless of the presence of warning symptoms or a history of serious gastrointestinal disease. If gastrointestinal bleeding occurs, the drug should be discontinued. The risk of gastrointestinal bleeding, ulceration or perforation increases with increasing NSAID dose, in patients with a history of ulcer, especially if complicated by bleeding or perforation, and in the elderly.

Elderly patients have an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation, sometimes fatal. Treatment of such patients should be started at the lowest possible dose.

Before starting the use of dexketoprofen trometamol in patients with a history of esophagitis, gastritis and/or peptic ulcer disease, it should be ensured that these diseases are in remission.

In patients with existing symptoms of gastrointestinal pathology and with a history of gastrointestinal diseases, it is necessary to monitor the condition of the digestive tract for possible disorders during the use of the drug, especially gastrointestinal bleeding.

NSAIDs should be used with caution in patients with a history of gastrointestinal diseases (ulcerative colitis, Crohn's disease), as these conditions may be exacerbated. The use of NSAIDs may lead to relapses of nonspecific ulcerative colitis, as well as Crohn's disease in patients who are in remission. For such patients and patients who use low-dose acetylsalicylic acid or other agents that increase the risk of gastrointestinal adverse reactions, combination therapy with protective drugs, such as misoprostol or proton pump inhibitors, should be considered.

Patients, especially the elderly, who have a history of adverse reactions from the gastrointestinal tract should inform their doctor about all unusual symptoms related to the digestive system, in particular gastrointestinal bleeding, especially in the initial stages of treatment.

Caution should be exercised when prescribing the drug to patients who are concomitantly taking agents that may increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants (e.g. warfarin), SSRIs or antiplatelet agents such as acetylsalicylic acid.

Patients with impaired renal function should be prescribed the drug with caution, since against the background of the use of NSAIDs, deterioration of renal function, fluid retention in the body and edema are possible. Due to the increased risk of nephrotoxicity, the drug should be prescribed with caution during treatment with diuretics, as well as in patients who may develop hypovolemia. During treatment, the body should receive a sufficient amount of fluid to avoid dehydration, which can lead to increased toxic effects on the kidneys. Like all NSAIDs, the drug may increase the concentration of urea nitrogen and creatinine in the blood plasma. Like other prostaglandin synthesis inhibitors, its use may be accompanied by adverse reactions from the kidneys, leading to glomerulonephritis, interstitial nephritis, papillary necrosis, nephrotic syndrome and acute renal failure. Most impaired renal function occurs in elderly patients.

Liver safety

Patients with impaired liver function should be prescribed the drug with caution. Like other NSAIDs, the drug may cause a temporary and slight increase in the values of some liver parameters, as well as a pronounced increase in the activity of AST and ALT. If these parameters increase, therapy should be discontinued.

Most liver dysfunction occurs in elderly patients.

Safety regarding the cardiovascular system and cerebral circulation

Patients with arterial hypertension and/or mild to moderate heart failure require monitoring and advice. Particular caution should be exercised when treating patients with a history of heart disease, in particular with previous episodes of heart failure (the risk of heart failure increases with the use of the drug), since fluid retention in the tissues and the formation of edema have been observed during treatment with NSAIDs. Clinical studies and epidemiological data suggest that the use of some NSAIDs (especially in high doses and for long periods) may be associated with a slightly increased risk of arterial thrombosis (for example, myocardial infarction or stroke). There is insufficient data to exclude such a risk with the use of dexketoprofen trometamol.

Therefore, in the case of uncontrolled hypertension, congestive heart failure, ischemic heart disease, peripheral arterial disease and/or cerebrovascular disease, dexketoprofen should be prescribed only after careful assessment of the patient's condition. An equally careful assessment should be carried out before starting long-term treatment in patients with risk factors for cardiovascular disease (such as hypertension, hyperlipidemia, diabetes mellitus, smoking).

Non-selective NSAIDs can reduce platelet aggregation and increase bleeding time by inhibiting prostaglandin synthesis. The simultaneous use of dexketoprofen trometamol and low molecular weight heparin in prophylactic doses in the postoperative period was studied in clinical studies, no effect on coagulation parameters was found. However, patients who use dexketoprofen trometamol simultaneously with drugs that affect hemostasis, such as warfarin, other coumarin drugs or heparins, should be under close medical supervision. The greatest number of cardiovascular system dysfunctions occurs in elderly patients.

Skin reactions

Very rare cases of serious skin reactions (some fatal) have been reported with NSAIDs, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis. Patients appear to be at greatest risk at the start of treatment, with most patients experiencing these reactions within the first month of treatment. The drug should be discontinued if skin rash, signs of mucosal involvement or other signs of hypersensitivity occur.

Other information

Particular caution should be exercised when prescribing the drug to patients:

- with hereditary disorders of porphyrin metabolism (for example, with acute intermittent porphyria);

- with dehydration;

- immediately after major surgical interventions.

If the doctor considers that long-term use of dexketoprofen is necessary, liver and kidney function should be monitored regularly.

In very rare cases, severe acute hypersensitivity reactions (e.g. anaphylactic shock) have been observed. At the first signs of severe hypersensitivity reactions after taking the medicinal product, treatment should be discontinued. Depending on the symptoms, any necessary treatment in such cases should be carried out under medical supervision.

Severe infectious complications of the skin and soft tissues may develop in association with chickenpox. Currently, there is no data to completely exclude the role of NSAIDs in the exacerbation of this infectious process. Therefore, the drug is not recommended for use in chickenpox.

The drug should be administered with caution to patients with hematopoietic disorders, systemic lupus erythematosus, and mixed connective tissue diseases.

As with other NSAIDs, dexketoprofen trometamol may mask the symptoms of infectious diseases during its use. In isolated cases, exacerbation of soft tissue infections has been reported during the use of NSAIDs. Therefore, if symptoms of a bacterial infection appear or worsen during use, patients are advised to consult a doctor immediately.

Each ampoule of the medicinal product contains 12.35% by volume of ethanol, i.e. 200 mg per dose, which is equivalent to 5 ml of beer or 2.08 glasses of wine per dose. The medicinal product may have adverse effects on persons suffering from alcoholism. The ethanol content should be taken into account when used in pregnant and lactating women, children and patients at risk, e.g. in patients with liver disease and epilepsy.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 'sodium-free'.

Use during pregnancy or breastfeeding

The use of the drug is contraindicated in the third trimester of pregnancy and during breastfeeding.

Pregnancy.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or fetal development. Epidemiological studies have shown that the use of drugs that inhibit prostaglandin synthesis in early pregnancy increases the risk of miscarriage, fetal heart defects, and anterior abdominal wall nonunion. Thus, the absolute risk of cardiovascular malformations increased with prostaglandins in animals, which caused an increase in pre- and post-implantation losses and increased embryo-fetal mortality. In addition, in animals treated with prostaglandin synthesis inhibitors during organogenesis, the incidence of fetal malformations, including cardiovascular anomalies, increased. However, studies of dexketoprofen trometamol in animals did not reveal toxicity to the reproductive organs. The appointment of dexketoprofen trometamol in the I and II trimesters of pregnancy is possible only in case of extreme necessity. When prescribing dexketoprofen trometamol to women planning pregnancy or during the first and second trimesters of pregnancy, the lowest possible effective dose should be used for the shortest possible duration of treatment.

During the third trimester, all prostaglandin synthesis inhibitors cause the following:

Risks to the fetus:

- cardiopulmonary toxic syndrome (with obstruction of the ductus arteriosus and pulmonary hypertension);

- impaired kidney function, which may progress to renal failure with the development of oligohydramnios.

Risks for mother and baby at the end of pregnancy:

- prolongation of bleeding time due to inhibition of platelet aggregation, which is possible even when using low doses;

- suppression of uterine contractile activity, which leads to prolongation and delay of labor.

Breastfeeding period.

There is no data on the penetration of dexketoprofen into breast milk. The drug is contraindicated during breastfeeding.

Fertility.

As with all NSAIDs, dexketoprofen trometamol may impair female fertility and is therefore not recommended in women attempting to conceive. In women who have difficulty conceiving or are undergoing investigation of infertility, discontinuation of the drug should be considered.

Ability to influence reaction speed when driving vehicles or other mechanisms

While using the drug, dizziness, visual disturbances or drowsiness may occur. In such cases, the ability to react quickly, navigate the road situation and drive vehicles or other mechanisms may deteriorate.

Method of administration and doses

Solution for intramuscular and intravenous administration.

Adults. The recommended dose is 50 mg every 8-12 hours. If necessary, a second dose should be administered after 6 hours. The maximum daily dose should not exceed 150 mg. The drug is intended for short-term use, therefore it should be used only during acute pain (no longer than 2 days). Patients should be transferred to oral analgesics, if possible. Adverse reactions can be reduced by using the minimum effective dose for the shortest possible time necessary to improve the condition. For moderate to severe postoperative pain, the drug can be used according to indications in the same recommended doses in combination with opioid analgesics.

Hepatic impairment. For patients with mild to moderate liver disease (Child-Pugh score 5-9), the maximum daily dose should be reduced to 50 mg and liver function should be closely monitored. The drug is contraindicated in severe liver disease (Child-Pugh score 10-15).

Renal impairment. In patients with mild renal impairment (creatinine clearance 60–89 ml/min), the maximum daily dose should be reduced to 50 mg. In patients with moderate or severe renal impairment (creatinine clearance 60–89 ml/min), the drug is contraindicated.

Children: The drug should not be used in children and adolescents due to a lack of data on safety and efficacy.

Method of application.

Intramuscular administration. The solution for injection should be injected slowly deep into the muscle.

Intravenous infusion. For intravenous infusion, the contents of a 2 ml ampoule should be diluted in 30–100 ml of 0.9% sodium chloride solution, 5% glucose solution or lactated Ringer's solution. The infusion solution should be prepared under aseptic conditions, avoiding exposure to natural daylight. The prepared solution should be clear. The infusion should be carried out within 10–30 minutes. Avoid exposure to natural daylight on the prepared solution.

The drug, diluted in 100 ml of 0.9% sodium chloride solution or in 5% glucose solution, is compatible with such drugs as dopamine, heparin, hydroxyzine, lidocaine, morphine, pethidine and theophylline.

The drug should not be mixed in an infusion solution with promethazine and pentazocine.

Intravenous injection (bolus administration). If necessary, the contents of one ampoule (2 ml of solution for injection) should be administered intravenously over at least 15 seconds.

The drug can be mixed in small volumes (e.g., in a syringe) with injectable solutions of heparin, lidocaine, morphine, and theophylline.

The drug should not be mixed in small volumes (e.g., in a syringe) with solutions of dopamine, promethazine, pentazocine, pethidine, and hydrocortisone because a white precipitate forms.

The medicine can only be mixed with the medicines listed above.

For intramuscular or intravenous injection, the drug should be administered immediately after withdrawal from the ampoule. The solution for intravenous infusion should be used immediately after preparation.

When storing diluted solutions of the drug in polyethylene bags or in products made of ethyl vinyl acetate, cellulose propionate, low-density polyethylene and polyvinyl chloride designed for administration, no changes in the content of the active substance due to sorption were observed.

The medicinal product is intended for single use, therefore the remains of the prepared solution should be disposed of. Before administering the medicinal product, it is necessary to make sure that the solution is clear and colorless. A solution containing solid particles should not be used.

Children.

The medicine should not be used in children and adolescents due to a lack of data on its efficacy and safety.

Overdose

Symptoms of overdose are unknown. Similar drugs cause disorders of the gastrointestinal tract (vomiting, anorexia, abdominal pain) and the nervous system (drowsiness, dizziness, disorientation, headache). In case of accidental overdose, symptomatic treatment should be immediately initiated according to the patient's condition. Dexketoprofen trometamol is removed from the body by dialysis.

Adverse reactions

The table below lists the adverse reactions, classified by organ system and frequency, whose relationship to dexketoprofen trometamol, according to clinical studies, is considered at least possible, as well as the adverse reactions that have been reported.

Gastrointestinal disorders were observed most frequently.

Possible development of peptic ulcer, perforation or gastrointestinal bleeding, sometimes fatal, especially in elderly patients. According to available data, nausea, vomiting, diarrhea, flatulence, constipation, dyspeptic phenomena, abdominal pain, melena, vomiting with blood, ulcerative stomatitis, exacerbation of colitis and Crohn's disease may occur against the background of the use of the drug.

Edema, hypertension, and heart failure, which may be caused by the use of NSAIDs, have also been reported.

As with other NSAIDs, the following adverse reactions are possible: aseptic meningitis, which mainly occurs in patients with systemic lupus erythematosus or mixed connective tissue diseases, and blood reactions (purpura, aplastic and hemolytic anemia, rarely - agranulocytosis and bone marrow hypoplasia).

Bullous reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis (very rare), are possible.

According to clinical trial results and epidemiological data, the use of some NSAIDs, especially in high doses and for long periods, may be associated with a slightly increased risk of developing pathologies caused by arterial thrombosis, such as myocardial infarction and stroke.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions occurring after the marketing authorisation of a medicinal product plays an important role. This allows for continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions via the national reporting system.

Expiration date

3 years.

After dilution, store the solution in a dark place at a temperature of 2 to 8 °C.