Роксера Комби

Uses

Patients with mild to moderate hypertension (alone or in combination with other antihypertensives).

The treatment of chronic stable and vasospastic angina.

Raynaud\'s disease.

Primary hypercholesterolemia (type IIa including heterozygous familial hypercholesterolemia), mixed dyslipidemia (type IIb), or homozygous familial hypercholesterolemia in patients who have not responded adequately to diet and other appropriate measures; prevention of cardiovascular events in patients at high risk of a first cardiovascular event.

Роксера Комби is also used to associated treatment for these conditions: Anginal Pain, Cardiovascular Events, Chronic Stable Angina Pectoris, Coronary Artery Disease (CAD), High Blood Pressure (Hypertension), Homozygous Familial Hypercholesterolemia, Hypertension,Essential, Mixed Dyslipidemias, Primary Hypercholesterolemia, Vasospastic AnginaAtherosclerosis, Atherosclerotic Cardiovascular Diseases, Cardiovascular Disease (CVD), Cardiovascular Events, Dysbetalipoproteinemia, Heterozygous Familial Hypercholesterolemia, High Blood Pressure (Hypertension), High Cholesterol, Homozygous Familial Hypercholesterolemia, Hypertension,Essential, Hypertriglyceridemias, Major Adverse Cardiovascular Events, Mixed Dyslipidemias, Postoperative Thromboembolism, Primary Hypercholesterolemia, Primary Hyperlipidemia, Cardiovascular Primary Prevention, Lipid-Lowering Therapy

How Роксера Комби works

Mechanism of action on blood pressure

Amlodipine is considered a peripheral arterial vasodilator that exerts its action directly on vascular smooth muscle to lead to a reduction in peripheral vascular resistance, causing a decrease in blood pressure. Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker) that inhibits the influx of calcium ions into both vascular smooth muscle and cardiac muscle. Experimental studies imply that amlodipine binds to both dihydropyridine and nondihydropyridine binding sites, located on cell membranes. The contraction of cardiac muscle and vascular smooth muscle are dependent on the movement of extracellular calcium ions into these cells by specific ion channels. Amlodipine blocks calcium ion influx across cell membranes with selectivity. A stronger effect of amlodipine is exerted on vascular smooth muscle cells than on cardiac muscle cells . Direct actions of amlodipine on vascular smooth muscle result in reduced blood pressure .

Mechanism of action in angina

The exact mechanism by which amlodipine relieves the symptoms of angina have not been fully elucidated to this date, however, the mechanism of action is likely twofold:

Amlodipine has a dilating effect on peripheral arterioles, reducing the total peripheral resistance (afterload) against which the cardiac muscle functions. Since the heart rate remains stable during amlodipine administration, the reduced work of the heart reduces both myocardial energy use and oxygen requirements .

Dilatation of the main coronary arteries and coronary arterioles, both in healthy and ischemic areas, is another possible mechanism of amlodipine reduction of blood pressure. The dilatation causes an increase in myocardial oxygen delivery in patients experiencing coronary artery spasm (Prinzmetal's or variant angina) and reduces coronary vasoconstriction caused by smoking .

Rosuvastatin is a statin medication and a competitive inhibitor of the enzyme HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase, which catalyzes the conversion of HMG-CoA to mevalonate, an early rate-limiting step in cholesterol biosynthesis. Rosuvastatin acts primarily in the liver, where decreased hepatic cholesterol concentrations stimulate the upregulation of hepatic low density lipoprotein (LDL) receptors which increases hepatic uptake of LDL. Rosuvastatin also inhibits hepatic synthesis of very low density lipoprotein (VLDL). The overall effect is a decrease in plasma LDL and VLDL.

In vitro and in vivo animal studies also demonstrate that rosuvastatin exerts vasculoprotective effects independent of its lipid-lowering properties, also known as the pleiotropic effects of statins. This includes improvement in endothelial function, enhanced stability of atherosclerotic plaques, reduced oxidative stress and inflammation, and inhibition of the thrombogenic response.

Statins have also been found to bind allosterically to β2 integrin function-associated antigen-1 (LFA-1), which plays an important role in leukocyte trafficking and in T cell activation.

Rosuvastatin exerts an anti-inflammatory effect on rat mesenteric microvascular endothelium by attenuating leukocyte rolling, adherence and transmigration. The drug also modulates nitric oxide synthase (NOS) expression and reduces ischemic-reperfusion injuries in rat hearts. Rosuvastatin increases the bioavailability of nitric oxide by upregulating NOS and by increasing the stability of NOS through post-transcriptional polyadenylation. It is unclear as to how rosuvastatin brings about these effects though they may be due to decreased concentrations of mevalonic acid.

Dosage

Роксера Комби dosage

For treatment of both hypertension and angina pectoris, the usual initial dose is 5 mg once daily. If the desired therapeutic effect cannot be achieved within 2-4 weeks, the dose may be increased to a maximum dose of 10 mg once daily. Amlodipine 10 mg once daily provides symptomatic improvement in patients with Raynaud's disease.

Use in children: Use of Amlodipine in children (under 12 years of age) is not recommended.

Before treatment initiation the patient should be placed on a standard cholesterol-lowering diet that should continue during treatment. The dose should be individualized according to the goal of therapy and patient response, using current consensus guidelines.

Treatment of hypercholesterolemia: Patient of Asian origin or with risk factors for myopathy or rhabdomyolysis: initially 5 mg once daily increased if necessary to max. 20 mg daily.

Prevention of cardiovascular events: Patient of Asian origin or with risk factors for myopathy or rhabdomyolysis: initially 5 mg once daily increased if necessary to max. 20 mg daily.

Pediatric Use (Hyperlipidemia including familial hypercholesterolemia):

• Child younger than 6 years: not recommended.
• Child 6–9 years: initially 5 mg daily, increased if necessary at intervals of at least 4 weeks to usual max. 10 mg once daily.
• Child 10–18 years: initially 5 mg daily, increased if necessary at intervals of at least 4 weeks to usual max. 20 mg once daily.

[Reduced dose required with concomitant atazanavir, darunavir, ezetimibe, fibrate, itraconazole, lopinavir, or tipranavir]

Use in the elderly (>70 years): A start dose of 5 mg is recommended. No dose adjustment necessary.

Renal insufficiency:Initially 5mg once daily (do not exceed 20 mg daily) if eGFR is 30-60 mL/minute/1.73 m2. Avoid if eGFR is less than 30 mL/minute/1.73 m2

Hepatic impairment:

• Child-Pugh scores of <7: no increase in systemic exposure to rosuvastatin.
• Child-Pugh scores of 8 and 9: increased systemic exposure has been observed. In these patients an assessment of renalfunction should be considered.
• Child-Pugh scores >9: no study.

Rosuvastatin is contraindicated in patients withactive liver disease.

Race: Increased systemic exposure has been seen in Asian subjects. The recommended starting dose is 5 mg for patients of Asian ancestry. The 40 mg dose is contraindicated in these patients.

Genetic polymorphisms: Specific types of genetic polymorphisms are known that can lead to increased rosuvastatin exposure. For patients who are known to have such specific types of polymorphisms, a lower daily dose of Rosuvastatin is recommended.

Dosage in patients with pre-disposing factors to myopathy: The recommended starting dose is 5 mg in patients with predisposing factors to myopathy. The 40 mg dose is contraindicated in some of these patients.

Rosuvastatin may be given at any time of day, with or without food

Side Effects

Amlodipine is generally well tolerated. The most commonly observed side effects are headache, peripheral oedema, palpitations, flushing, dizziness, nausea, abdominal pain.

Common or very common: Proteinuria.

Rare: Hepatitis, jaundice.

Very rare: Gynecomastia, hematuria, hepati failure, interstitial lung disease, lupus erythematosus-like reactions, pancreatitis.

Frequency not known: Alopecia, altered liver function tests, amnesia, arthralgia, asthenia, depression, dizziness, edema, fatigue, gastrointestinal disturbances, headache, hypersensitivity reactions, hyperglycemia -may be associated with the development of diabetes mellitus (particularly in those already at risk of the condition), myalgia, myopathy, myositis, paresthesia, peripheral neuropathy, pruritus, rash, rhabdomyolysis, sexual dysfunction, sleep disturbance, Stevens-Johnson syndrome, thrombocytopenia, urticaria, visual disturbance.

Muscle effects: The risk of myopathy, myositis, and rhabdomyolysis associated with statin use is rare. Although myalgia has been reported commonly in patients receiving statins, muscle toxicity truly attributable to statin use is rare. Muscle toxicity can occur with all statins, however the likelihood increases with higher doses If muscular symptoms or raised creatine kinase occur during treatment, other possible causes (e.g. rigorous physical activity, hypothyroidism, infection, recent trauma, and drug or alcohol addiction) should be excluded before statin therapy is implicated, particularly if statin treatment has previously been tolerated for more than 3 months. When a statin is suspected to be the cause of myopathy, and creatine kinase concentration is markedly elevated (more than 5 times upper limit of normal), or if muscular symptoms are severe, treatment should be discontinued. If symptoms resolve and creatine kinase concentrations return to normal, the statin should be reintroduced at a lower dose and the patient monitored closely; an alternative statin should be prescribed if unacceptable side-effects are experienced with a particular statin. Statins should not be discontinued in the event of small, asymptomatic elevations of creatine kinase. Routine monitoring of creatine kinase is unnecessary in asymptomatic patients.Statins should not be discontinued if there is an increase in the blood-glucose concentration or HbA1C as the benefits continue to outweigh the risks.

Interstitial lung disease: If patients develop symptoms such as dyspnoea, cough, and weight loss, they should seek medical attention.

Toxicity

Acute oral toxicity (LD50): 37 mg/kg (mouse) .

Overdose

An overdose of amlodipine could result in a high degree of peripheral vasodilatation with a possibility of reflex tachycardia. Significant and prolonged hypotension leading to shock and fatal outcomes have been reported .

Carcinogenesis, mutagenesis, impairment of fertility

Rats and mice treated with amlodipine maleate in the diet on a long-term basis for up to 2 years demonstrated no evidence of a carcinogenic effect of the drug. For the mouse, the highest dose was comparable to the maximum recommended human dose of 10 mg amlodipine per day. For the rat, the highest dose was measured to be about twice the maximum recommended human dose .

Mutagenicity studies using amlodipine maleate showed no drug-related gene or chromosomal effects .

There was no impact on the fertility of rats given oral amlodipine maleate (males for 64 days and females for 14 days before mating) at doses up to 10 mg amlodipine/kg/day (8 times the maximum recommended human dose) .

Use in pregnancy

The safety of amlodipine in human pregnancy or lactation has not been proven. Amlodipine is therefore considered a pregnancy category C drug . Use amlodipine only if the potential benefit justifies the potential risk .

Use in nursing

Discontinue when administering amlodipine .

Generally well-tolerated. Side effects may include myalgia, constipation, asthenia, abdominal pain, and nausea. Other possible side effects include myotoxicity (myopathy, myositis, rhabdomyolysis) and hepatotoxicity. To avoid toxicity in Asian patients, lower doses should be considered. Pharmacokinetic studies show an approximately two-fold increase in peak plasma concentration and AUC in Asian patients (Philippino, Chinese, Japanese, Korean, Vietnamese, or Asian-Indian descent) compared to Caucasian patients.

Precaution

Hypotension: Since the vasodilUse in renal failure

Although Amlodipine is excreted primarily via kidney, mild renal impairment does not appear to have an effect on the plasma concentrations. Severe renal impairment may however require a dosage reduction. Amlodipine is not dialyzable.

Use in patients with impaired hepatic function

Amlodipine half-life is prolonged in patient with impaired hepatic function. Amlodipine should therefore be administered at lower (5mg) initial dose in these patients.

Use in heart failure

An increased number of pulmonary oedema has been reported.atation induced by Amlodipine is gradual in onset, acute hypotension has rarely been reported after oral administration of Amlodipine. Nonetheless, caution should be exercised when administering the drug with any other peripheral vasodilator particularly in patients with severe aortic stenosis.

Cardiac failure: Patients with heart failure should be treated with caution. Calcium channel blockers, including Amlodipine, should be usedwith caution in patients with congestive heart failure, as they may increase the risk of future cardiovascular events and mortality.

Beta blocker withdrawal: Amlodipine gives no protection against the danger of abrupt beta blocker withdrawal; any such withdrawal should be gradualreduction of the dose of beta blocker.

Hepatic failure: The half-life of amlodipine is prolonged and AUC values are higher in patients with impaired liver function. Amlodipine should therefore be initiated at the lower end of the dosing range and caution should be used, both on initial treatment and when increasing the dose. Slow dose titration and careful monitoring may be required in patients with severe hepatic impairment.

Hypothyroidism should be managed adequately before starting treatment with a statin. Statins should be used with caution in those with a history of liver disease or with a high alcohol intake. There is little information available on a rational approach to liver-function monitoring; however, a NICE guideline1 suggests that liver enzymes should be measured before treatment, and repeated within 3 months and at 12 months of starting treatment, unless indicated at other times by signs or symptoms suggestive of hepatotoxicity. Those with serum transaminases that are raised, but less than 3 times the upper limit of the reference range, should not be routinely excluded from statin therapy. Those with serum transaminases of more than 3 times the upper limit of the reference range should discontinue statin therapy.

Statins should be used with caution in those with risk factors for myopathy or rhabdomyolysis; patients should be advised to report unexplained muscle pain. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose galactose malabsorption should not take this medicine.

Interaction

Use of Amlodipine together with thiazide diuretics or angiotensin-converting-enzyme inhibitors in the treatment of hypertension is additive. There are no hazardous interaction of Amlodipine with Digoxin, Cimetidine, Warfarin and food.

Cyclosporine: Cyclosporine increased rosuvastatin exposure (AUC) 7-fold. Therefore, in patients taking cyclosporine, the dose of Rosuvastatin should not exceed 5 mg once daily.

Gemfibrozil: Gemfibrozil significantly increased rosuvastatin exposure. Due to an observed increased risk of myopathy/rhabdomyolysis, combination therapy with Rosuvastatin and gemfibrozil should be avoided. If used together, the dose of Rosuvastatin should not exceed 10 mg once daily.

Protease Inhibitors: Coadministration of rosuvastatin with certain protease inhibitors has differing effects on rosuvastatin exposure. Simeprevir, which is a hepatitis C virus (HCV) protease inhibitor, or combinations of atazanavir/ritonavir or lopinavir/ritonavir, which are HIV-1 protease inhibitors, increase rosuvastatin exposure (AUC) up to threefold. For these protease inhibitors, the dose of Rosuvastatin should not exceed 10 mg once daily. The combinations of fosamprenavir / ritonavir or tipranavir / ritonavir, which are HIV 1 protease inhibitors, produce little or no change in rosuvastatin exposure. Caution should be exercised when rosuvastatin is coadministered with protease inhibitors.

Coumarin Anticoagulants: Rosuvastatin significantly increased INR in patients receiving coumarin anticoagulants. Therefore, caution should be exercised when coumarin anticoagulants are given in conjunction with Rosuvastatin. In patients taking coumarin anticoagulants and Rosuvastatin concomitantly, INR should be determined before starting Rosuvastatin and frequently enough during early therapy to ensure that no significant alteration of INR occurs.

Niacin: The risk of skeletal muscle effects may be enhanced when Rosuvastatin is used in combination with lipid-modifying doses (>1 g/day) of niacin; caution should be used when prescribing with Rosuvastatin.

Fenofibrate: When Rosuvastatin was coadministered with fenofibrate, no clinically significant increase in the AUC of rosuvastatin or fenofibrate was observed. Because it is known that the risk of myopathy during treatment with statins is increased with concomitant use of fenofibrates, caution should be used when prescribing fenofibrates with Rosuvastatin.

Colchicine: Cases of myopathy, including rhabdomyolysis, have been reported with statins, including rosuvastatin, coadministered with colchicine, and caution should be exercised when prescribing Rosuvastatin with colchicine

Volume of Distribution

21 L/kg , .

Rosuvastatin undergoes first-pass extraction in the liver, which is the primary site of cholesterol synthesis and LDL-C clearance. The mean volume of distribution at steady-state of rosuvastatin is approximately 134 litres.

Elimination Route

Amlodipine absorbed slowly and almost completely from the gastrointestinal tract. Peak plasma concentrations are achieved 6-12 hours after oral administration. The estimated bioavailability of amlodipine is 64-90%. Steady-state plasma amlodipine levels are achieved after 7-8 days of consecutive daily dosing. Absorption is not affected by food .

In a study of healthy white male volunteers, the absolute oral bioavailability of rosuvastatin was found to be approximately 20% while absorption was estimated to be 50%, which is consistent with a substantial first-pass effect after oral dosing. Another study in healthy volunteers found that the peak plasma concentration (Cmax) of rosuvastatin was 6.06ng/mL and was reached at a median of 5 hours following oral dosing. Both Cmax and AUC increased in approximate proportion to dose. Neither food nor evening versus morning administration was shown to have an effect on the AUC of rosuvastatin. Many statins are known to interact with hepatic uptake transporters and thus reach high concentrations at their site of action in the liver.

Breast Cancer Resistance Protein (BCRP) is a membrane-bound protein that plays an important role in the absorption of rosuvastatin, particularly as CYP3A4 has minimal involvement in its metabolism. Evidence from pharmacogenetic studies of c.421C>A single nucleotide polymorphisms (SNPs) in the gene for BCRP has demonstrated that individuals with the 421AA genotype have reduced functional activity and 2.4-fold higher AUC and Cmax values for rosuvastatin compared to study individuals with the control 421CC genotype. This has important implications for the variation in response to the drug in terms of efficacy and toxicity, particularly as the BCRP c.421C>A polymorphism occurs more frequently in Asian populations than in Caucasians. Other statin drugs impacted by this polymorphism include fluvastatin and atorvastatin.

Genetic differences in the OATP1B1 (organic-anion-transporting polypeptide 1B1) hepatic transporter have also been shown to impact rosuvastatin pharmacokinetics. Evidence from pharmacogenetic studies of the c.521T>C SNP showed that rosuvastatin AUC was increased 1.62-fold for individuals homozygous for 521CC compared to homozygous 521TT individuals. Other statin drugs impacted by this polymorphism include simvastatin, pitavastatin, atorvastatin, and pravastatin.

For patients known to have the above-mentioned c.421AA BCRP or c.521CC OATP1B1 genotypes, a maximum daily dose of 20mg of rosuvastatin is recommended to avoid adverse effects from the increased exposure to the drug, such as muscle pain and risk of rhabdomyolysis.

Half Life

The terminal elimination half-life of about 30–50 hours .

Plasma elimination half-life is 56 hours in patients with impaired hepatic function, titrate slowly when administering this drug to patients with severe hepatic impairment .

The elimination half-life (t½) of rosuvastatin is approximately 19 hours and does not increase with increasing doses.

Clearance

Total body clearance (CL) has been calculated as 7 ± 1.3 ml/min/kg (0.42 ± 0.078 L/ h/kg) in healthy volunteers , .

Elderly patients show a reduced clearance of amlodipine with an AUC (area under the curve) increase of about 40–60%, and a lower initial dose may be required .

Elimination Route

Elimination from the plasma occurs in a biphasic with a terminal elimination half-life of about 30–50 hours. Steady-state plasma levels of amlodipine are reached after 7-8 days of consecutive daily dosing . Amlodipine is 10% excreted as unchanged drug in the urine. Amlodipine can be initiated at normal doses in patients diagnosed with renal failure , .

Rosuvastatin is not extensively metabolized; approximately 10% of a radiolabeled dose is recovered as metabolite. Following oral administration, rosuvastatin and its metabolites are primarily excreted in the feces (90%). After an intravenous dose, approximately 28% of total body clearance was via the renal route, and 72% by the hepatic route.

A study in healthy adult male volunteers found that approximately 90% of the rosuvastatin dose was recovered in feces within 72 hours after dose, while the remaining 10% was recovered in urine. The drug was completely excreted from the body after 10 days of dosing. They also found that approximately 76.8% of the excreted dose was unchanged from the parent compound, with the remaining dose recovered as the metabolites n-desmethyl rosuvastatin and rosuvastatin-5S-lactone.

Renal tubular secretion is responsible for >90% of total renal clearance, and is believed to be mediated primarily by the uptake transporter OAT3 (Organic anion transporter 1), while OAT1 had minimal involvement.

Pregnancy & Breastfeeding use

Pregnancy: Safety in pregnancy has not been established.

Lactation: It is not known whether Amlodipine is excreted in breast milk. It is advised to stop breastfeeding during treatment with Amlodipine.

Pregnancy Category X. Teratogenic effects. Rosuvastatin is contraindicated in pregnancy and lactation. Women of child bearing potential should use appropriate contraceptive measures. If a patient becomes pregnant during use of this product, treatment should be discontinued immediately.

Rosuvastatin is excreted in the milk of rats. There are no data with respect to excretion in milk in humans

Contraindication

Amlodipine is contraindicated in patients with-

• Hypersensitivity to amlodipine, dihydropyridine derivatives or any of the excipients
• Shock (including cardiogenic shock)
• Obstruction of the outflow-tract of the left ventricle (e.g. high grade aortic stenosis)
• Unstable angina
• Hemodynamically unstable heart failure after acute myocardial infarction (during the first 28 days)
• Severe hypotension

Rosuvastatin is contraindicated:

• In patients with hypersensitivity to rosuvastatin or to any of the excipients.
• In patients with active liver disease including unexplained, persistent elevations of serum transaminases and any serum transaminase elevation exceeding 3 x the upper limit of normal (ULN).
• In patients with severe renal impairment (creatinine clearance < mL/minute/1.73m2).
• In patients with myopathy.
• In patients receiving concomitant cyclosporine.
• During pregnancy and lactation and in women of childbearing potential not using appropriate contraceptive measures.

Special Warning

Children with hypertension from 6 years to 17 years of age: 2.5 mg once daily as a starting dose, up-titrated to 5 mg once daily if blood pressure goal is not achieved after 4 weeks. Doses in excess of 5 mg daily have not been studied in pediatric patients.

Children under 6 years old: The effect of amlodipine on blood pressure in patients less than 6 years of age is not known.

Elderly: Amlodipine used at similar doses in elderly or younger patients is equally well tolerated. Normal dosage regimens are recommended in the elderly, but increase of the dosage should take place with care.

Renal impairment: Changes in amlodipine plasma concentrations are not correlated with degree of renal impairment, therefore the normal dosage is recommended. Amlodipine is not dialysable.

Hepatic impairment: Dosage recommendations have not been established in patients with mild to moderate hepatic impairment; therefore dose selection should be cautions and should start at the lower end of the dosing range. The pharmacokinetics of Amlodipine have not been studied in severe hepatic impairment. Amlodipine should be initiated at the lowest dose (2.5 mg once daily) and titrated slowly in patients with severe hepatic impairment.

Age and sex: There was no clinically relevant effect of age or sex on the pharmacokinetics of Rosuvastatin in adults.

Race: Pharmacokinetic studies show an increase in exposure in Asian subjects compared with Caucasians.

Severe renal impairment (not on hemodialysis): Starting dose is 5 mg, not to exceed 10 mg

Use in the elderly: Patients > 70 years: A start dose of 5 mg is recommended. No dose adjustment necessary.

Renal insufficiency: Initially 5mg once daily (do not exceed 20mg daily) if eGFR is 30–60 mL/ minute/ 1.73 m2. Avoid if eGFR is less than 30 mL /minute/ 1.73 m2.

Genetic polymorphisms: Specific types of genetic polymorphisms are known that can lead to increased rosuvastatin exposure. For patients who are known to have such specific types of polymorphisms, a lower daily dose of Rosuvastatin is recommended.

Dosage in patients with pre-disposing factors to myopathy: The recommended starting dose is 5 mg in patients with predisposing factors to myopathy. The 40 mg dose is contraindicated in some of these patients.

Acute Overdose

There is no well documented experience with Amlodipine overdosage. In case of clinically significant hypotension due to Amlodipine over dosage, calls for active cardiovascular support including monitoring of cardiac and respiratory function, elevation of extremities and attention to circulating fluid volume and urine output. Since Amlodipine is highly protein-bound, dialysis is unlikely to be of benefit.

There is no specific treatment in the event of overdose. In the event of overdose, the patient should be treated symptomatically and supportive measures instituted as required. Haemodialysis is unlikely to be of benefit.

Storage Condition

Keep out of the reach of children. Store below 30° C. Keep in the original package in a cool & dry place in order to protect from light and moisture.

Keep out of the reach of children. Store below 30° C. Keep in the original package in a cool & dry place in order to protect from light and moisture.

Innovators Monograph

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