Avexus

Avexus: Avexus 250 mg, Immediate-Release Tablet: One tablet contains 250mg Avexus. Tablet sodium content: 3.4 mg tablet.

Avexus Forte: Avexus 500 mg, Immediate-Release Tablet: One tablet contains 500mg Avexus. Tablet sodium content: 6.1 mg tablet.

Avexus MR: Avexus 500 mg, Modified-Release Tablet: One tablet contains 500 mg Avexus.

Avexus Paediatric Suspension 125 mg/5 mL: Avexus 125 mg/5 ml, Granules for

Oral Suspension (Pediatric Suspension): Each 5 ml of the granules for suspension contains 125 mg of Avexus.

Avexus Paediatric Suspension 250 mg/5 mL: Avexus 250 mg/5 ml, Granules for

Oral Suspension (Pediatric Suspension): Each 5 ml of the granules for suspension contains 250 mg of Avexus.

Avexus is a semisynthetic macrolide antibiotic obtained by substitution of a CH₃O group for the hydroxyl (OH) group in position 6 of the erythromycin lactonic ring. Specifically, Avexus is 6-O-methyl erythromycin A. The white to off-white antibiotic powder is practically odorless, essentially insoluble in water and slightly soluble in ethanol, methanol and acetonitrile. Its molecular weight is 747.96.

Avexus Paediatric Suspension is an oral dosage form of Avexus for use primarily in children.

Excipients/Inactive Ingredients: Avexus: Tablet Core: Croscarmellose sodium, pregelatinized starch, microcrystalline cellulose, quinoline yellow (E104 aluminium lake), silicon dioxide, povidone, stearic acid, magnesium stearate, talc. Tablet Coating, Colour and Gloss Coating: Hypromellose, sorbitan monooleate, propylene glycol, titanium dioxide, vanillin, quinoline yellow (E104 aluminium lake), hydroxypropyl cellulose, sorbic acid.

Avexus Forte: Tablet Core: Croscarmellose sodium, microcrystalline cellulose, silicon dioxide, povidone, stearic acid, magnesium stearate, talc. Tablet Coating, Colour and Gloss Coating: Hypromellose, sorbitan monooleate, propylene glycol, titanium dioxide, vanillin, quinoline yellow (E104 aluminium lake), hydroxypropyl cellulose, sorbic acid.

Avexus MR: Tablet Core: Citric acid, sodium alginate, sodium calcium alginate, lactose, povidone, talc, stearic acid, magnesium stearate. Coating Solution: Hypromellose, polyethylene glycol, titanium dioxide, quinoline yellow (E104 aluminium lake), sorbic acid.

Avexus Paediatric Suspension: Granule Component and Coating: Carbopol carbomers, povidone, hypromellose phthalate, castor oil. Other Ingredients: Sucrose, xanthan gum, silicon dioxide, potassium sorbate, citric acid, maltodextrin, titanium dioxide, fruit punch flavor.

Acute Bacterial Exacerbation of Chronic Bronchitis

Avexus (Filmtab, Granules) and Avexus XL Filmtab are indicated in adults for the treatment of mild to moderate infections caused by susceptible isolates due to Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, or Streptococcus pneumoniae.

Acute Maxillary Sinusitis

Avexus (Filmtab, Granules) and Avexus XL Filmtab (in adults) are indicated for the treatment of mild to moderate infections caused by susceptible isolates due to Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae.

Community-Acquired Pneumonia

Avexus (Filmtab, Granules) and Avexus XL Filmtab are indicated for the treatment of mild to moderate infections caused by susceptible isolates due to:

• Haemophilus influenzae (in adults)

• Haemophilus parainfluenzae (Avexus XL Filmtab in adults)

• Moraxella catarrhalis (Avexus XL Filmtab in adults)

• Mycoplasma pneumoniae, Streptococcus pneumoniae, Chlamydophila pneumoniae (Avexus XL Filmtab [in adults]; Avexus Filmtab and Avexus Granules [in adults and pediatric patients])

Pharyngitis/Tonsillitis

Avexus Filmtab and Avexus Granules are indicated for the treatment of mild to moderate infections caused by susceptible isolates due to Streptococcus pyogenes as an alternative in individuals who cannot use first line therapy.

Uncomplicated Skin and Skin Structure Infections

Avexus Filmtab and Avexus Granules are indicated for the treatment of mild to moderate infections caused by susceptible isolates due to Staphylococcus aureus, or Streptococcus pyogenes.

Acute Otitis Media

Avexus Filmtab and Avexus Granules are indicated in pediatric patients for the treatment of mild to moderate infections caused by susceptible isolates due to Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae.

Treatment and Prophylaxis of Disseminated Mycobacterial Infections

Avexus Filmtab and Avexus Granules are indicated for the treatment of mild to moderate infections caused by susceptible isolates due to Mycobacterium avium or Mycobacterium intracellulare in patients with advanced HIV infection.

Helicobacter pylori Infection and Duodenal Ulcer Disease

Avexus Filmtab is given in combination with other drugs in adults as described below to eradicate H. pylori. The eradication of H. pylori has been demonstrated to reduce the risk of duodenal ulcer recurrence.

• Avexus Filmtab in combination with amoxicillin and PREVACID (lansoprazole) or PRILOSEC (omeprazole) Delayed-Release Capsules, as triple therapy, are indicated for the treatment of patients with H. pylori infection and duodenal ulcer disease (active or five-year history of duodenal ulcer) to eradicate H. pylori.
• Avexus Filmtab in combination with PRILOSEC (omeprazole) capsules are indicated for the treatment of patients with an active duodenal ulcer associated with H. pylori infection. Regimens which contain Avexus Filmtab as the single antibacterial agent are more likely to be associated with the development of Avexus resistance among patients who fail therapy. Avexus-containing regimens should not be used in patients with known or suspected Avexus resistant isolates because the efficacy of treatment is reduced in this setting.

Limitations of Use

Avexus XL Filmtab is indicated only for acute maxillary sinusitis, acute bacterial exacerbation of chronic bronchitis, and community-acquired pneumonia in adults. The efficacy and safety of Avexus XL Filmtab in treating other infections for which Avexus Filmtab and Avexus Granules are approved have not been established.

There is resistance to macrolides in certain bacterial infections caused by Streptococcus pneumoniae and Staphylococcus aureus. Susceptibility testing should be performed when clinically indicated.

Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Avexus and other antibacterial drugs, Avexus should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Avexus is used to treat bacterial infections in many different parts of the body. It is also used in combination with other medicines to treat duodenal ulcers caused by H. pylori. Avexus is also used to prevent and treat Mycobacterium avium complex (MAC) infection.

Avexus belongs to the class of medicines known as macrolide antibiotics. It works by killing bacteria or preventing their growth. However, Avexus will not work for colds, flu, or other virus infections.

Avexus is available only with your doctor's prescription.

Once a medicine has been approved for marketing for a certain use, experience may show that it is also useful for other medical problems. Although this use is not included in product labeling, Avexus is used in certain patients with the following medical condition:

• Legionnaires' disease.

Avexus/Avexus Forte: Respiratory Tract/Skin and Soft Tissue Infections: Adults and Children ≥12 years: Usual Dose: 250 mg twice daily for 7 days, although this may be increased to 500 mg twice daily for up to 14 days in severe infections.

Children <12 years: Use Avexus Paediatric Suspension. The use of Avexus IR has not been studied in children <12 years.

Eradication of H. pylori: Adults and Elderly Triple Therapy Regimen: Avexus 500 mg twice daily in conjunction with amoxicillin 1000 mg twice daily and a proton-pump inhibitor in standard dose twice daily for 7 days.

Dual Therapy Regimen: Avexus 500 mg 3 times daily in conjunction with omeprazole 40 mg once daily for 14 days, followed by omeprazole 40 mg once daily for an additional 14 days. Supportive studies have been conducted with omeprazole 40 mg once daily for 14 days.

Renal Impairment: Dosage adjustments are not usually required except in patients with severe renal impairment (creatinine clearance <30 mL/min). If adjustment is necessary, the total daily dosage should be reduced by ½ eg, 250 mg once daily or 250 mg twice daily in more severe infections.

Avexus may be given without regard to meals as food does not affect the extent of bioavailability.

Avexus MR: Adults and Children >12 years: Usual Recommended

Dosage: 1 modified-release tab daily to be taken with food. In more severe infections, the dosage can be increased to 2 tabs daily. The usual duration of treatment is 7-14 days.

Children <12 years: Use Avexus Paediatric Suspension. The use of Avexus MR has not been studied in children <12 years.

Renal Impairment: Avexus MR should not be used in patients with renal impairment (creatinine clearance <30 mL/min). Avexus immediate-release tablets may be used in this patient population.

Do not crush or chew Avexus MR tablets.

Avexus Paediatric Suspension: Children 6 months to 12 years: Clinical trials have been conducted using Avexus Pediatric Suspension in children 6 months-12 years. Therefore, children 6 months-12 years of age should use Avexus Pediatric Suspension (granules for oral suspension).

Recommended Daily

Dosage: 7.5 mg/kg twice daily up to a maximum dose of 500 mg twice daily for nonmycobacterial infections. The usual duration of treatment is for 5-10 days depending on the pathogen involved and the severity of the condition. The prepared suspension can be taken with or without meals, and can be taken with milk.

Table 3 is a suggested guide for determining

Dosage: See Table 3.

Patients with Renal Impairment: In children with creatinine clearance <30 mL/min, the dosage of Avexus should be reduced by ½ ie, up to 250 mg once daily or 250 mg twice daily in more severe infections. Dosage should not be continued >14 days in these patients.

Patients with Mycobacterial Infections: In children with disseminated or localized mycobacterial infections (M. avium, M. intracellulare, M. chelonae, M. fortuitum, M. kansasii), the recommended dose is 15-30 mg/kg/day in 2 divided doses.

Treatment with Avexus should continue as long as clinical benefit is demonstrated. The addition of other antimycobacterial agents may be of benefit.

See also:
What is the most important information I should know about Avexus?

Hypersensitivity

Avexus is contraindicated in patients with a known hypersensitivity to Avexus, erythromycin, or any of the macrolide antibacterial drugs.

Cardiac Arrhythmias

Concomitant administration of Avexus with cisapride and pimozide is contraindicated [seeDRUG INTERACTIONS (7)].

There have been postmarketing reports of drug interactions when Avexus is coadministered with cisapride or pimozide, resulting in cardiac arrhythmias (QT prolongation, ventricular tachycardia, ventricular fibrillation, and torsades de pointes) most likely due to inhibition of metabolism of these drugs by Avexus. Fatalities have been reported.

Cholestatic Jaundice/Hepatic Dysfunction

Avexus is contraindicated in patients with a history of cholestatic jaundice or hepatic dysfunction associated with prior use of Avexus.

Colchicine

Concomitant administration of Avexus and colchicine is contraindicated in patients with renal or hepatic impairment.

HMG-CoA Reductase Inhibitors

Do not use Avexus concomitantly with HMG-CoA reductase inhibitors (statins) that are extensively metabolized by CYP3A4 (lovastatin or simvastatin), due to the increased risk of myopathy, including rhabdomyolysis.

Ergot Alkaloids

Concomitant administration of Avexus and ergotamine or dihydroergotamine is contraindicated.

Contraindications for Coadministered Drugs

For information about contraindications of other drugs indicated in combination with Avexus, refer to their full prescribing information (contraindications section).

Use Avexus extended-release tablets as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Take Avexus extended-release tablets by mouth with food.
• Swallow Avexus extended-release tablets whole. Do not break, crush, or chew before swallowing.
• If you are also taking zidovudine, do not take it within 2 hours before or after Avexus extended-release tablets.
• Avexus extended-release tablets works best if it is taken at the same time each day.
• To clear up your infection completely, take Avexus extended-release tablets for the full course of treatment. Keep taking it even if you feel better in a few days.
• Do not miss any doses. If you miss a dose of Avexus extended-release tablets, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Avexus extended-release tablets.

Use: Labeled Indications

Chronic obstructive pulmonary disease, acute exacerbation: Treatment of acute bacterial exacerbation of chronic bronchitis in adults due to susceptible Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, or Streptococcus pneumoniae.

Helicobacter pylori eradication: Eradication of Helicobacter pylori to reduce the risk of duodenal ulcer recurrence as a component of combination therapy (triple therapy) in adults with H. pylori infection and duodenal ulcer disease (active or 5-year history of duodenal ulcer).

Limitations of use: Regimens that contain Avexus as the single antibacterial agent are more likely to be associated with the development of Avexus resistance. Avexus-containing regimens should not be used in patients with known or suspected Avexus-resistant isolates (efficacy is reduced).

Mycobacterial (nontuberculous) infection: Prophylaxis and treatment of disseminated mycobacterial infections due to Mycobacterium avium complex (MAC) in patients with advanced HIV infection.

Otitis media: Treatment of acute otitis media in pediatric patients due to susceptible H. influenzae, M. catarrhalis, or S. pneumoniae.

Pneumonia, community-acquired: Treatment of community-acquired pneumonia due to susceptible Mycoplasma pneumoniae, S. pneumoniae, or Chlamydophila pneumoniae (adult and pediatric patients) and H. influenzae, H. parainfluenzae, or M. catarrhalis (adults).

Skin/skin structure infection: Treatment of uncomplicated skin/skin structure infection due to susceptible Staphylococcus aureus or Streptococcus pyogenes.

Streptococcal pharyngitis: Treatment of pharyngitis/tonsillitis due to susceptible S. pyogenes (alternative agent for patients with severe penicillin allergy).

Off Label Uses

Bartonella spp. infection

Based on the US Department of Health and Human Services guidelines for prevention and treatment of opportunistic infections in adults and adolescents with HIV, Avexus is an effective and recommended alternative agent for treatment or long-term suppression of bartonellosis infection.

Clinical experience also suggests the utility of Avexus for the treatment of cat scratch disease.

See also:
What other drugs will affect Avexus?

Avexus: Data available to date indicate that Avexus is metabolized primarily by the hepatic cytochrome P-450 3A (CYP3A) isozyme. This is an important mechanism determining many drug interactions.

The metabolism of other drugs by this system may be inhibited by concomitant administration with Avexus and may be associated with elevations in serum levels of drug classes known or suspected to be metabolized by the same CYP450 and CYP3A isozyme.

Other Drug Interactions: Elevated digoxin serum concentrations have been reported in patients receiving Avexus tablets and digoxin concomitantly. Monitoring of serum digoxin levels should be considered.

There have been post-marketing reports of Torsades de pointes occurring with concurrent use of Avexus and quinidine or disopyramide. Serum levels of these medications should be monitored during Avexus therapy.

Rhabdomyolysis coincident with the co-administration of Avexus and the HMG-CoA reductase inhibitors eg, lovastatin and simvastatin has rarely been reported.

Antiretroviral Drug Interactions: Simultaneous oral administration of Avexus tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Because Avexus appears to interfere with the absorption of simultaneously administered oral zidovudine, this interaction can be largely avoided by staggering the doses of Avexus and zidovudine. This interaction does not appear to occur in pediatric HIV-infected patients taking Avexus suspension with zidovudine or dideoxyinosine.

A pharmacokinetic study demonstrated that the concomitant administration of ritonavir 200 mg every 8 hrs and Avexus 500 mg every 12 hrs resulted in a marked inhibition of the metabolism of Avexus.

For patients with renal impairment, the following dosage adjustments should be considered: For patients with CrCl 30-60 mL/min, the dose of Avexus should be reduced by 50%. For patients with CrCl <30 mL, the dose of Avexus should be decreased by 75%. Doses of Avexus >1 g/day should not be co-administered with ritonavir.

Avexus OD: As with other macrolide antibiotics, the use of Avexus in patients concurrently taking drugs metabolized by the cytochrome P-450 system (eg, cilostazol, methylprednisolone, anticoagulants eg, warfarin, quinidine, sildenafil, ergot alkaloids, alprazolam, triazolam, midazolam, disopyramide, lovastatin, rifabutin, phenytoin, cyclosporin, vinblastine, valproate and tacrolimus) may be associated with elevations in serum levels of these other drugs.

Digoxin: Elevated digoxin serum concentrations have been reported in patients receiving Avexus tablets and digoxin concomitantly. Monitoring of serum digoxin levels should be considered.

Quinidine/Disopyramide: There have been post-marketed reports of Torsades de pointes occurring with concurrent use of Avexus and quinidine or disopyramide. Electrocardiogram and serum levels of these medications should be monitored during Avexus therapy.

HMG-CoA Reductase Inhibitors: As with other macrolides, Avexus has been reported to increase concentrations of HMG-CoA reductase inhibitors (eg, statins). Rhabdomyolysis has also been reported in patients taking these drugs concomitantly.

Theophylline, Carbamazepine: The administration of Avexus to patients receiving theophylline or carbamazepine has been associated with an increase in serum theophylline or carbamazepine levels.

Oral Anticoagulants:

Ritonavir: Ritonavir increases AUC, C_max and C_min of Avexus when administered concurrently. Because of the large therapeutic window for Avexus, no dosage reduction should be necessary in patients with normal renal function. However, for patients with renal impairment, the following dosage adjustments should be considered: For patients with CrCl 30-60 mL/min, the dose of Avexus should be reduced by 50%. For patients with CrCl <30 mL/min, the dose of Avexus should be decreased by 75%. Doses of Avexus >1 g/day should not be co-administered with ritonavir.

Efavirenz, Nevirapine, Rifampicin and Rifabutin: Strong inducers of the cytochrome P-450 metabolism system eg, efavirenz, nevirapine, rifampicin and rifabutin may accelerate the metabolism of Avexus and thus, lower the plasma levels of Avexus. Since the microbiological activities of Avexus and 14-OH-Avexus are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of Avexus and enzyme inducers.

Sildenafil, Tadalafil and Vardenafil: Each of these phosphodiesterase inhibitors is metabolized, at least in part, by CYP3A, and CYP3A may be inhibited by concomitantly administered Avexus. Reduction in sildenafil, tadalafil and vardenafil dosages should be considered when these drugs are co-administered with Avexus.

Triazolam: Drug interactions and CNS effects (eg, somnolence and confusion) with the concomitant use of Avexus and triazolam have been reported. Monitoring the patient for increased CNS pharmacological effects is suggested.

Colchicine: When Avexus and colchicine are administered together, inhibition of Pgp and/or CYP3A by Avexus may lead to increased exposure to colchicine. Patients should be monitored for clinical symptoms of colchicine toxicity.

Itraconazole: Both Avexus and itraconazole are substrates and inhibitors of CYP3A. Avexus may increase the plasma levels of itraconazole, while itraconazole may increase the plasma levels of Avexus. Patients taking itraconazole and Avexus concomitantly should be monitored closely for signs and symptoms of increased or prolonged pharmacological effect.

Zidovudine: Simultaneous oral administration of Avexus tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. This interaction does not appear to occur in pediatric HIV-infected patients taking Avexus suspension with zidovudine or dideoxyinosine.

See also:
What are the possible side effects of Avexus?

the most frequently reported events in adults taking Avexus tablets (Avexus tablets, USP) were diarrhea (3%), nausea (3%), abnormal taste (3%), dyspepsia (2%), abdominal pain/discomfort (2%), and headache (2%). In pediatric patients, the most frequently reported events were diarrhea (6%), vomiting (6%), abdominal pain (3%), rash (3%), and headache (2%). Most of these events were described as mild or moderate in severity. Of the reported adverse events, only 1% was described as severe.

The most frequently reported events in adults taking Avexus XL (Avexus extended-release tablets) were diarrhea (6%), abnormal taste (7%), and nausea (3%). Most of these events were described as mild or moderate in severity. Of the reported adverse events, less than 1% were described as severe.

In the acute exacerbation of chronic bronchitis and acute maxillary sinusitis studies overall gastrointestinal adverse events were reported by a similar proportion of patients taking either Avexus tablets or Avexus XL tablets; however, patients taking Avexus XL tablets reported significantly less severe gastrointestinal symptoms compared to patients taking Avexus tablets. In addition, patients taking Avexus XL tablets had significantly fewer premature discontinuations for drug-related gastrointestinal or abnormal taste adverse events compared to Avexus tablets.

In community-acquired pneumonia studies conducted in adults comparing Avexus to erythromycin base or erythromycin stearate, there were fewer adverse events involving the digestive system in Avexus-treated patients compared to erythromycin-treated patients (13% vs 32%; p < 0.01). Twenty percent of erythromycin-treated patients discontinued therapy due to adverse events compared to 4% of Avexus-treated patients.

In two U.S. studies of acute otitis media comparing Avexus to amoxicillin/potassium clavulanate in pediatric patients, there were fewer adverse events involving the digestive system in Avexus-treated patients compared to amoxicillin/potassium clavulanate-treated patients (21% vs. 40%, p < 0.001). One-third as many Avexus-treated patients reported diarrhea as did amoxicillin/potassium clavulanate-treated patients.

Post-Marketing Experience

Allergic reactions ranging from urticaria and mild skin eruptions to rare cases of anaphylaxis, Stevens-Johnson syndrome and toxic epidermal necrolysis have occurred. Other spontaneously reported adverse events include glossitis, stomatitis, oral moniliasis, anorexia, vomiting, pancreatitis, tongue discoloration, thrombocytopenia, leukopenia, neutropenia, and dizziness. There have been reports of tooth discoloration in patients treated with Avexus. Tooth discoloration is usually reversible with professional dental cleaning. There have been isolated reports of hearing loss, which is usually reversible, occurring chiefly in elderly women. Reports of alterations of the sense of smell including smell loss, usually in conjunction with taste perversion or taste loss, have also been reported.

Transient CNS events including anxiety, behavioral changes, confusional states, convulsions, depersonalization, disorientation, hallucinations, insomnia, depression, manic behavior, nightmares, psychosis, tinnitus, tremor, and vertigo have been reported during post-marketing surveillance. Events usually resolve with discontinuation of the drug.

Hepatic dysfunction, including increased liver enzymes, and hepatocellular and/or cholestatic hepatitis, with or without jaundice, has been infrequently reported with Avexus. This hepatic dysfunction may be severe and is usually reversible. In very rare instances, hepatic failure with fatal outcome has been reported and generally has been associated with serious underlying diseases and/or concomitant medications.

There have been rare reports of hypoglycemia, some of which have occurred in patients taking oral hypoglycemic agents or insulin.

There have been post-marketing reports of tablets in the stool, many of which have occurred in patients with anatomic (including ileostomy or colostomy) or functional gastrointestinal disorders with shortened GI transit times.

As with other macrolides, Avexus has been associated with QT prolongation and ventricular arrhythmias, including ventricular tachycardia and torsades de pointes.

There have been reports of interstitial nephritis coincident with Avexus use.

There have been post-marketing reports of colchicine toxicity with concomitant use of Avexus and colchicine, especially in the elderly, some of which occurred in patients with renal insufficiency.

Deaths have been reported in some such patients.

Changes in Laboratory Values

Changes in laboratory values with possible clinical significance were as follows:

Hepatic

Elevated SGPT (ALT) < 1%; SGOT (AST) < 1%; GGT < 1%; alkaline phosphatase < 1%; LDH < 1%; total bilirubin < 1%

Hematologic

Decreased WBC < 1%; elevated prothrombin time 1%

Renal

Elevated BUN 4%; elevated serum creatinine < 1%

GGT, alkaline phosphatase, and prothrombin time data are from adult studies only.