Summary of Product Characteristics Updated 14-Oct-2022 | Flamingo Pharma (UK) Ltd
Amoxicillin 125mg/5ml Powder for Oral Suspension Sugar Free
Amoxicillin 125mg/5ml Powder for Oral Suspension Sugar Free contains Amoxicillin Trihydrate BP equivalent to Amoxicillin BP 125mg.
Excipients with known effect
Contains sodium benzoate
Contains sorbitol
For the full list of excipients, see section 6.1.
Pale yellow powder for reconstitution as suspension.
Amoxicillin Powder for Oral Suspension Sugar Free is indicated for the treatment of the following infections in adults and children (see sections 4.2, 4.4 and 5.1) such as:
• Acute bacterial sinusitis
• Acute otitis media
• Acute streptococcal tonsillitis and pharyngitis
• Acute exacerbations of chronic bronchitis
• Community acquired pneumonia
• Acute cystitis
• Asymptomatic bacteriuria in pregnancy
• Acute pyelonephritis
• Typhoid and paratyphoid fever
• Dental abscess with spreading cellulitis
• Prosthetic joint infections
• Helicobacter pylori eradication
• Lyme disease
Amoxicillin Powder for Oral Suspension Sugar Free is also indicated for the prophylaxis of endocarditis.
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
Posology
The dose of Amoxicillin Powder for Oral Suspension Sugar Free that is selected to treat an individual infection should take into account:
• The expected pathogens and their likely susceptibility to antibacterial agents (see section 4.4)
• The severity and the site of the infection
• The age, weight and renal function of the patient; as shown below
The duration of therapy should be determined by the type of infection and the response of the patient and should generally be as short as possible. Some infections require longer periods of treatment (see section 4.4 regarding prolonged therapy).
Adults and children ≥ 40 kg
| Indication* | Dose* |
| Acute bacterial sinusitis Asymptomatic bacteriuria in pregnancy | 250 mg to 500 mg every 8 hours or 750 mg to 1g every 12 hours |
| Acute pyelonephritis Dental abscess with spreading cellulitis | For severe infections 750 mg to 1 g every 8 hours |
| Acute cystitis | Acute cystitis may be treated with 3 g twice daily for one day |
| Acute otitis media Acute streptococcal tonsillitis and pharyngitis Acute exacerbations of chronic bronchitis | 500 mg every 8 hours, 750 mg to 1 g every 12 hours For severe infections 750 mg to 1 g every 8 hours for 10 days |
| Community acquired pneumonia | 500 mg to 1 g every 8 hours |
| Typhoid and paratyphoid fever | 500 mg to 2 g every 8 hours |
| Prosthetic joint infections | 500 mg to 1 g every 8 hours |
| Prophylaxis of endocarditis | 2 g orally, single dose 30 to 60 minutes before procedure |
| Helicobacter pylori eradication | 750 mg to 1 g twice daily in combination with a proton pump inhibitor (e.g. omeprazole, lansoprazole) and another antibiotic (e.g. clarithromycin, metronidazole) for 7 days |
| Lyme disease (see section 4.4) | Early stage: 500 mg to 1 g every 8 hours up to a maximum of 4 g/day in divided doses for 14 days (10 to 21 days) Late stage (systemic involvement): 500 mg to 2 g every 8 hours up to a maximum of 6 g/day in divided doses for 10 to 30 days |
| *Consideration should be given to the official treatment guidelines for each indication | |
Children weighing < 40 kg
Children may be treated with Amoxicillin Capsules, dispersible tablets suspensions or sachets.
Amoxicillin Paediatric Suspension is recommended for children under six months of age.
Children weighing 40 kg or more should be prescribed the adult dosage.
Recommended doses:
| Indication+ | Dose+ |
| Acute bacterial sinusitis Acute otitis media Community acquired pneumonia Acute cystitis Acute pyelonephritis Dental abscess with spreading cellulitis | 20 to 90 mg/kg/day in divided doses* |
| Acute streptococcal tonsillitis and pharyngitis | 40 to 90 mg/kg/day in divided doses* |
| Typhoid and paratyphoid fever | 100 mg/kg/day in three divided doses |
| + Consideration should be given to the official treatment guidelines for each indication. *Twice daily dosing regimens should only be considered when the dose is in the upper range. | |
Elderly
No dose adjustment is considered necessary.
Renal impairment
| GFR (ml/min) | Adults and children ≥ 40 kg | Children < 40 kg# |
| greater than 30 | no adjustment necessary | no adjustment necessary |
| 10 to 30 | maximum 500 mg twice daily | 15 mg/kg given twice daily |
| less than 10 | maximum 500 mg/day. | 15 mg/kg given as a single daily dose |
| # In the majority of cases, parenteral therapy is preferred. | ||
In patients receiving haemodialysis
Amoxicillin may be removed from the circulation by haemodialysis.
| Haemodialysis | |
| Adults and children over 40 kg | 500 mg every 24 h Prior to haemodialysis one additional dose of 500 mg should be administered. In order to restore circulating drug levels, another dose of 500 mg should be administered after haemodialysis. |
| Children under 40 kg | 15 mg/kg/day given as a single daily dose (maximum 500 mg). Prior to haemodialysis one additional dose of 15 mg/kg should be administered. In order to restore circulating drug levels, another dose of 15 mg/kg should be administered after haemodialysis. |
In patients receiving peritoneal dialysis
Amoxicillin maximum 500 mg/day.
Hepatic impairment
Dose with caution and monitor hepatic function at regular intervals (see sections 4.4 and 4.8).
Method of administration
Amoxicillin Powder for Oral Suspension Sugar Free is for oral use.
Absorption of Amoxicillin Powder for Oral Suspension Sugar Free is unimpaired by food. Therapy can be started parenterally according to the dosing recommendations of the intravenous formulation and continued with an oral preparation.
For instructions on reconstitution of the medicinal product before administration, see section 6.6.
Hypersensitivity to the active substance, to any of the penicillins or to any of the excipients listed in section 6.1.
History of a severe immediate hypersensitivity reaction (e.g. anaphylaxis) to another betalactam agent (e.g. a cephalosporin, carbapenem or monobactam).
Hypersensitivity reactions
Before initiating therapy with any penicillin, careful enquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins or other beta-lactam agents (see sections 4.3 and 4.8).
Serious and occasionally fatal hypersensitivity reactions (including anaphylactoid and severe cutaneous adverse reactions) have been reported in patients on penicillin therapy. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and in atopic individuals. If an allergic reaction occurs, amoxicillin therapy must be discontinued and appropriate alternative therapy instituted.
Non-susceptible microorganisms
Amoxicillin is not suitable for the treatment of some types of infection unless the pathogen is already documented and known to be susceptible or there is a very high likelihood that the pathogen would be suitable for treatment with amoxicillin (see section 5.1). This particularly applies when considering the treatment of patients with urinary tract infections and severe infections of the ear, nose and throat.
Convulsions
Convulsions may occur in patients with impaired renal function or in those receiving high doses or in patients with predisposing factors (e.g. history of seizures, treated epilepsy or meningeal disorders (see section 4.8).
Renal impairment
In patients with renal impairment, the dose should be adjusted according to the degree of impairment (see section 4.2).
Skin reactions
The occurrence at the treatment initiation of a feverish generalised erythema associated with pustula may be a symptom of acute generalised exanthemous pustulosis (AEGP, see section 4.8). This reaction requires amoxicillin discontinuation and contra-indicates any subsequent administration.
Amoxicillin should be avoided if infectious mononucleosis is suspected since the occurrence of a morbilliform rash has been associated with this condition following the use of amoxicillin.
Jarisch-Herxheimer reaction
The Jarisch-Herxheimer reaction has been seen following amoxicillin treatment of Lyme disease (see section 4.8). It results directly from the bactericidal activity of amoxicillin on the causative bacteria of Lyme disease, the spirochaete Borrelia burgdorferi. Patients should be reassured that this is a common and usually self- limiting consequence of antibiotic treatment of Lyme disease.
Overgrowth of non-susceptible microorganisms
Prolonged use may occasionally result in overgrowth of non-susceptible organisms.
Antibiotic-associated colitis has been reported with nearly all antibacterial agents and may range in severity from mild to life threatening (see section 4.8). Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during, or subsequent to, the administration of any antibiotics. Should antibiotic-associated colitis occur, amoxicillin should immediately be discontinued, a physician consulted and an appropriate therapy initiated. Anti- peristaltic medicinal products are contra-indicated in this situation.
Prolonged therapy
Periodic assessment of organ system functions; including renal, hepatic and haematopoietic function is advisable during prolonged therapy. Elevated liver enzymes and changes in blood counts have been reported (see section 4.8).
Anticoagulants
Prolongation of prothrombin time has been reported rarely in patients receiving amoxicillin. Appropriate monitoring should be undertaken when anticoagulants are prescribed concomitantly. Adjustments in the dose of oral anticoagulants may be necessary to maintain the desired level of anticoagulation (see section 4.5 and 4.8).
Crystalluria
In patients with reduced urine output, crystalluria has been observed very rarely, predominantly with parenteral therapy. During the administration of high doses of amoxicillin, it is advisable to maintain adequate fluid intake and urinary output in order to reduce the possibility of amoxicillin crystalluria. In patients with bladder catheters, a regular check of patency should be maintained (see section 4.8 and 4.9).
Interference with diagnostic tests
Elevated serum and urinary levels of amoxicillin are likely to affect certain laboratory tests. Due to the high urinary concentrations of amoxicillin, false positive readings are common with chemical methods.
It is recommended that when testing for the presence of glucose in urine during amoxicillin treatment, enzymatic glucose oxidase methods should be used.
The presence of amoxicillin may distort assay results for oestriol in pregnant women.
Probenecid
Concomitant use of probenecid is not recommended. Probenecid decreases the renal tubular secretion of amoxicillin. Concomitant use of probenecid may result in increased and prolonged blood levels of amoxicillin.
Allopurinol
Concurrent administration of allopurinol during treatment with amoxicillin can increase the likelihood of allergic skin reactions.
Tetracyclines
Tetracyclines and other bacteriostatic drugs may interfere with the bactericidal effects of amoxicillin.
Oral anticoagulants
Oral anticoagulants and penicillin antibiotics have been widely used in practice without reports of interaction. However, in the literature there are cases of increased international normalised ratio in patients maintained on acenocoumarol or warfarin and prescribed a course of amoxicillin. If co- administration is necessary, the prothrombin time or international normalised ratio should be carefully monitored with the addition or withdrawal of amoxicillin. Moreover, adjustments in the dose of oral anticoagulants may be necessary (see sections 4.4 and 4.8).
Methotrexate
Penicillins may reduce the excretion of methotrexate causing a potential increase in toxicity.
Oral typhoid vaccine
The oral typhoid vaccine is inactivated by antibacterials.
Important Information about excipients
This medicinal product contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.
This medicinal product contains sodium benzoate which is a mild irritant to the eyes, skin and mucous membrane. May increase the risk of jaundice in newborn babies.
Pregnancy
Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. Limited data on the use of amoxicillin during pregnancy in humans do not indicate an increased risk of congenital malformations.
Amoxicillin may be used in pregnancy when the potential benefits outweigh the potential risks associated with treatment.
Breastfeeding
Amoxicillin is excreted into breast milk in small quantities with the possible risk of sensitisation. Consequently, diarrhoea and fungus infection of the mucous membranes are possible in the breast-fed infant, so that breast-feeding might have to be discontinued. Amoxicillin should only be used during breast-feeding after benefit/risk assessment by the physician in charge.
Fertility
There are no data on the effects of amoxicillin on fertility in humans. Reproductive studies in animals have shown no effects on fertility.
No studies on the effects on the ability to drive and use machines have been performed. However, undesirable effects may occur (e.g. allergic reactions, dizziness, convulsions), which may influence the ability to drive and use machines (see section 4.8).
The most commonly reported adverse drug reactions (ADRs) are diarrhoea, nausea and skin rash.
The ADRs derived from clinical studies and post-marketing surveillance with amoxicillin, presented by MedDRA System Organ Class are listed below.
The following terminologies have been used in order to classify the occurrence of undesirable effects.
Very common (≥ 1/10)
Common (≥ 1/100 to <1/10)
Uncommon (≥ 1/1,000 to <1/100)
Rare (≥ 1/10,000 to <1/1,000)
Very rare (<1/10,000)
Not known (cannot be estimated from the available data)
| Infections and infestations | |
| Very rare | Mucocutaneous candidiasis |
| Blood and lymphatic system disorders | |
| Very rare | Reversible leucopenia (including severe neutropenia or agranulocytosis), reversible thrombocytopenia and haemolytic anaemia. Prolongation of bleeding time and prothrombin time (see section 4.4). |
| Immune system disorders | |
| Very rare | Severe allergic reactions, including angioneurotic oedema, anaphylaxis, serum sickness and hypersensitivity vasculitis (see section 4.4). |
| Not known | Jarisch-Herxheimer reaction (see section 4.4). |
| Nervous system disorders | |
| Very rare | Hyperkinesia, dizziness and convulsions (see section 4.4). |
| Gastrointestinal disorders | |
| Clinical Trial Data | |
| *Common | Diarrhoea and nausea |
| *Uncommon | Vomiting |
| Post-marketing Data | |
| Very rare | Antibiotic associated colitis (including pseudomembraneous colitis and haemorrhagic colitis see section 4.4). Black hairy tongue Superficial tooth discolouration# |
| Hepatobiliary disorders | |
| Very rare | Hepatitis and cholestatic jaundice. A moderate rise in AST and/or ALT. |
| Skin and subcutaneous tissue disorders | |
| Clinical Trial Data | |
| *Common | Skin rash |
| *Uncommon | Urticaria and pruritus |
| Post-marketing Data | |
| Very rare | Skin reactions such as erythema multiforme, Stevens- Johnson syndrome, toxic epidermal necrolysis, bullous and exfoliative dermatitis, acute generalised exanthematous pustulosis (AGEP) (see section 4.4) and drug reaction with eosinophilia and systemic symptoms (DRESS). |
| Renal and urinary tract disorders | |
| Very rare: | Interstitial nephritis Crystalluria (see sections 4.4 and 4.9 Overdose) |
| * The incidence of these AEs was derived from clinical studies involving a total of approximately 6,000 adult and paediatric patients taking amoxicillin. #Superficial tooth discolouration has been reported in children. Good oral hygiene may help to prevent tooth discolouration as it can usually be removed by brushing | |
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store. By reporting side effects you can help provide more information on the safety of this medicine.
Symptoms and signs of overdose
Gastrointestinal symptoms (such as nausea, vomiting and diarrhoea) and disturbance of the fluid and electrolyte balances may be evident. Amoxicillin crystalluria, in some cases leading to renal failure, has been observed.
Convulsions may occur in patients with impaired renal function or in those receiving high doses (see sections 4.4 and 4.8).
Treatment of intoxication
Gastrointestinal symptoms may be treated symptomatically, with attention to the water/electrolyte balance.
Amoxicillin can be removed from the circulation by haemodialysis.
Pharmacotherapeutic group: penicillins with extended spectrum; ATC code: J01CA04.
Mechanism of action
Amoxicillin is a semisynthetic penicillin (beta-lactam antibiotic) that inhibits one or more enzymes (often referred to as penicillin-binding proteins, PBPs) in the biosynthetic pathway of bacterial peptidoglycan, which is an integral structural component of the bacterial cell wall. Inhibition of peptidoglycan synthesis leads to weakening of the cell wall, which is usually followed by cell lysis and death.
Amoxicillin is susceptible to degradation by beta-lactamases produced by resistant bacteria and therefore the spectrum of activity of amoxicillin alone does not include organisms which produce these enzymes.
Pharmacokinetic/pharmacodynamic relationship
The time above the minimum inhibitory concentration (T>MIC) is considered to be the major determinant of efficacy for amoxicillin.
Mechanisms of resistance
The main mechanisms of resistance to amoxicillin are:
• Inactivation by bacterial beta-lactamases.
• Alteration of PBPs, which reduce the affinity of the antibacterial agent for the target.
Impermeability of bacteria or efflux pump mechanisms may cause or contribute to bacterial resistance, particularly in Gram-negative bacteria.
Breakpoints
MIC breakpoints for amoxicillin are those of the European Committee on Antimicrobial Susceptibility Testing (EUCAST) version 5.0.
| Organism | MIC breakpoint (mg/L) | |
| Susceptible ≤ | Resistant > | |
| Enterobacteriaceae | 81 | 8 |
| Staphylococcus spp. | Note2 | Note 2 |
| Enterococcus spp.3 | 4 | 8 |
| Streptococcus groups A, B, C and G | Note 4 | Note 4 |
| Streptococcus pneumoniae | Note 5 | Note 5 |
| Viridans group steprococci | 0.5 | 2 |
| Haemophilus influenzae | 26 | 26 |
| Moraxella catarrhalis | Note 7 | Note 7 |
| Neisseria meningitidis | 0.125 | 1 |
| Gram positive anaerobes except Clostridium difficile8 | 4 | 8 |
| Gram negative anaerobes8 | 0.5 | 2 |
| Helicobacter pylori | 0.1259 | 0.1259 |
| Pasteurella multocida | 1 | 1 |
| Non- species related breakpoints10 | 2 | 8 |
| 1Wild type Enterobacteriaceae are categorised as susceptible to aminopenicillins. Some countries prefer to categorise wild type isolates of E. coli and P. mirabilis as intermediate. When this is the case, use the MIC breakpoint S ≤ 0.5 mg/L 2Most staphylococci are penicillinase producers, which are resistant to amoxicillin. Methicillin resistant isolates are, with few exceptions, resistant to all beta-lactam agents. 3Susceptibility to amoxicillin can be inferred from ampicillin 4The susceptibility of streptococcus groups A, B, C and G to penicillins is inferred from the benzylpenicillin susceptibility. 5Breakpoints relate only to non-meningitis isolates. For isolates categorised as intermediate to ampicillin avoid oral treatment with amoxicillin. Susceptibility inferred from the MIC of ampicillin. 6Breakpoints are based on intravenous administration. Beta-lactamase positive isolates should be reported resistant. 7Beta lactamase producers should be reported resistant 8Susceptibility to amoxicillin can be inferred from benzylpenicillin. 9The breakpoints are based on epidemiological cut-off values (ECOFFs), which distinguish wild-type isolates from those with reduced susceptibility. 10The non-species related breakpoints are based on doses of at least 0.5 g x 3or 4 doses daily (1.5 to 2 g/day). | ||
The prevalence of resistance may vary geographically and with time for selected species, and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.
| In vitro susceptibility of micro-organisms to Amoxicillin |
| Commonly Susceptible Species |
| Gram-positive aerobes: Enterococcus faecalis Beta-hemolytic streptococci (Groups A, B, C and G) Listeria monocytogenes |
| Species for which acquired resistance may be a problem |
| Gram-negative aerobes: Escherichia coli Haemophilus influenzae Helicobacter pylori Proteus mirabilis Salmonella typhi Salmonella paratyphi Pasteurella multocida |
| Gram-positive aerobes: Coagulase negative staphylococcus Staphylococcus aureus£ Streptococcus pneumoniae Viridans group streptococcus |
| Gram-positive anaerobes: Clostridium spp. |
| Gram-negative anaerobes: Fusobacterium spp. |
| Other: Borrelia burgdorferi |
| Inherently resistant organisms† |
| Gram-positive aerobes: Enterococcus faecium† |
| Gram-negative aerobes: Acinetobacter spp. Enterobacter spp. Klebsiella spp. Pseudomonas spp. |
| Gram-negative anaerobes: Bacteroides spp. (many strains of Bacteroides fragilis are resistant). |
| Others: Chlamydia spp. Mycoplasma spp. Legionella spp. |
| † Natural intermediate susceptibility in the absence of acquired mechanism of resistance. £ Almost all S.aureus are resistant to amoxilcillin due to production of penicillinase. In addition, all methicillin-resistant strains are resistant to amoxicillin. |
Absorption
Amoxicillin fully dissociates in aqueous solution at physiological pH. It is rapidly and well absorbed by the oral route of administration. Following oral administration, amoxicillin is approximately 70% bioavailable. The time to peak plasma concentration (Tmax) is approximately one hour.
The pharmacokinetic results for a study, in which an amoxicillin dose of 250 mg three times daily was administered in the fasting state to groups of healthy volunteers are presented below.
| Cmax | Tmax * | AUC (0-24h) | T ½ |
| (μ g/ml) | (h) | (μ g.h/ml) | (h) |
| 3.3 ± 1.12 | 1.5 (1.0-2.0) | 26.7 ± 4.56 | 1.36 ± 0.56 |
| *Median (range) | |||
In the range 250 to 3000 mg the bioavailability is linear in proportion to dose (measured as Cmax and AUC). The absorption is not influenced by simultaneous food intake.
Haemodialysis can be used for elimination of amoxicillin.
Distribution
About 18% of total plasma amoxicillin is bound to protein and the apparent volume of distribution is around 0.3 to 0.4 l/kg.
Following intravenous administration, amoxicillin has been found in gall bladder, abdominal tissue, skin, fat, muscle tissues, synovial and peritoneal fluids, bile and pus. Amoxicillin does not adequately distribute into the cerebrospinal fluid.
From animal studies there is no evidence for significant tissue retention of drug- derived material. Amoxicillin, like most penicillins, can be detected in breast milk (see section 4.6).
Amoxicillin has been shown to cross the placental barrier (see section 4.6).
Biotransformation
Amoxicillin is partly excreted in the urine as the inactive penicilloic acid in quantities equivalent to up to 10 to 25% of the initial dose.
Elimination
The major route of elimination for amoxicillin is via the kidney.
Amoxicillin has a mean elimination half-life of approximately one hour and a mean total clearance of approximately 25 l/hour in healthy subjects. Approximately 60 to 70% of the amoxicillin is excreted unchanged in urine during the first 6 hours after administration of a single 250 mg or 500 mg dose of amoxicillin. Various studies have found the urinary excretion to be 50-85% for amoxicillin over a 24 hour period.
Concomitant use of probenecid delays amoxicillin excretion (see section 4.5).
Age
The elimination half-life of amoxicillin is similar for children aged around 3 months to 2 years and older children and adults. For very young children (including preterm newborns) in the first week of life the interval of administration should not exceed twice daily administration due to immaturity of the renal pathway of elimination. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
Gender
Following oral administration of amoxicillin/ to healthy males and female subjects, gender has no significant impact on the pharmacokinetics of amoxicillin.
Renal impairment
The total serum clearance of amoxicillin decreases proportionately with decreasing renal function (see sections 4.2 and 4.4).
Hepatic impairment
Hepatically impaired patients should be dosed with caution and hepatic function monitored at regular intervals.
Non-clinical data reveal no special hazard for humans based on studies of safety pharmacology, repeated dose toxicity, genotoxicity and toxicity to reproduction and development.
Carcinogenicity studies have not been conducted with amoxicillin.
Sodium Benzoate
Disodium Edetate
Sodium Citrate
Citric Acid
Colloidal Anhydrous Silica
Sorbitol
Saccharin Sodium
Banana Flavour
Quinoline Yellow, E104
Xantham Gum
None Known.
3 years unopened.
7 days after reconstitution.
Do not store above 25° C.
High density polyethylene bottles with tamper-evident and child resistant cap of the appropriate size to accommodate 100ml.
And
High density polyethylene bottles with tamper-evident cap of the appropriate size to accommodate 100ml.
Quantities of potable water to be added are: 84ml to reconstitute 100ml of 125/5ml Amoxicillin Sugar Free Suspension.
Flamingo Pharma UK Limited
1st Floor Kirkland House
11-15 Peterborough Road Harrow,
Middlesex, HA1 2AX
PL 43461/0074
15/10/2021
15/10/2021
The BLOC, 38 Springfield Way, Kingston Upon Hull, HU10 6RJ, UK
00 800 890 13370
+44 (0) 7784240228
http://www.flamingopharma.co.uk
