Zenith Suspension

Azithromycin monohydrate.

The active substance of azithromycin monohydrate (Zenith) 200 mg/5 mL powder for oral suspension is azithromycin monohydrate equivalent to 200 mg azithromycin per 5 mL.

Pharmacology: Pharmacodynamics: Azithromycin monohydrate (Zenith) is an azalide, derived from the macrolide class of antibiotics. The mode of action of Azithromycin monohydrate (Zenith)is inhibition of protein synthesis in bacteria by binding to the 50s ribosomal subunit and preventing translocation of peptides. Azithromycin monohydrate 9Zenith) is usually bacteriostatic. However, in high concentrations, azithromycin may be bactericidal against selected microorganisms. Azithromycin monohydrate (Zenith) is active against many gram-positive and gram-negative aerobic and anaerobic bacteria and bacterial pathogens such as Mycobacterium avium complex, Mycoplasma spp, Borrelia burgdorferi, Chlamydia spp and Campylobacter spp. In addition, Azithromycin monohydrate (Zenith) has activity against protozoan microorganisms such as Toxoplasma gondii.
Breakpoints: According to the (CLSI) Clinical and Laboratory Standards Institute in 2001, the following breakpoints have been defined for azithromycin: 2 μg/mL susceptible; 4 μg/mL intermediate; ≥8 μg/mL resistant. Haemophilus spp: ≤4 μg/mL susceptible. Streptococcus pneumoniae and Streptococcus pyogenes: ≤0.5 μg/mL susceptible; 1 μg/mL intermediate; ≥2 μg/mL resistant.
Note that national breakpoints may differ from those recommended by CLSI. There are currently no recommended CLSI breakpoints for Enterobacteriaceae, Neisseria gonorrhoeae, Moraxella catarrhalis and Mycobacterium avium complex.
Susceptibility: The prevalence of acquired 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. (See Table 1.)

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Other Information: The diagnostic procedures available in vitro at this moment to determine the susceptibility of Mycobacterium avium complex (MAC) organisms are not generally accepted and validated.
Streptococci and staphylococci that are resistant to erythromycin are also resistant to Azithromycin monohydrate (Zenith). Cross-resistance to Mycobacterium avium complex organisms occurs between clarithromycin and azithromycin.
Pharmacokinetics: Absorption: After oral administration, the bioavailability of Azithromycin monohydrate (Zenith) is approximately 37%. Peak plasma levels are reached after 2-3 hours (C_max after a single dose of 500 mg orally was approximately 0.4 mg/L).
Distribution: Kinetic studies have shown markedly higher Azithromycin monohydrate (Zenith) levels in tissue than in plasma (up to 50 times the maximum observed concentration in plasma) indicating that the active substance is heavily tissue bound (steady-state distribution volume of approximately 31 L/kg). Concentrations in target tissues eg, lung, tonsil, and prostate exceed the MIC₉₀ so for likely pathogens after a single dose of 500 mg.
In experimental in vitro and in vivo studies, Azithromycin monohydrate (Zenith) accumulates in the phagocytes, freeing is stimulated by active phagocytosis. In animal studies, this process appeared to contribute to the accumulation of Azithromycin monohydrate (Zenith) in the tissue.
In serum the protein binding of Azithromycin monohydrate (Zenith) is variable and depending on the serum concentration varies from 50% in 0.05 mg/L to 12% in 0.5 mg/L.
Excretion: Plasma terminal elimination half-life closely reflects the tissue depletion half-life of 2 to 4 days. About 12% of an IV administered dose is excreted in the urine unchanged over a period of 3 days; the majority in the first 24 hours. Biliary excretion of Azithromycin monohydrate (Zenith), predominantly in unchanged form, is a major route of elimination.
The identified metabolites (formed by N- and O-demethylizing, by hydroxylizing of the desosamine and aglycone rings, and by the splitting of the cladinose conjugate) are microbiologically inactive.
After a 5 day treatment, slightly higher (29%) AUC values were seen in the elderly volunteers (>65 years) compared to the younger volunteers (<45 years). However these differences are not regarded as clinically relevant; therefore a dose adjustment is not recommended.
Special Populations: Renal insufficiency: Following a single oral dose of azithromycin 1 g, mean C_max and AUC_0-120 increased by 5.1% and 4.2%, respectively, in subjects with mild to moderate renal impairment (glomerular filtration rate of 10-80 mL/min) compared with normal renal function (GFR >80 mL/min). In subjects with severe renal impairment, the mean C_max and AUC_0-120 increased 61% and 35%, respectively compared to normal.
Hepatic insufficiency: In patients with mild to moderate hepatic impairment, there is no evidence of a marked change in serum pharmacokinetics of azithromycin monohydrate compared to normal hepatic function. In these patients, urinary recovery of Azithromycin monohydrate (Zenith) appears to increase perhaps to compensate for reduced hepatic clearance.
Elderly: The pharmacokinetics of azithromycin in elderly men was similar to that of young adults; however, in elderly women, although higher peak concentrations (increased by 30-50%) were observed, no significant accumulation occurred.
Infants, toddlers, children and adolescents: Pharmacokinetics have been studied in children 4 months - 15 years taking capsules, granules or suspension. At 10 mg/kg on day 1 followed by 5 mg/kg on days 2-5, the C_max achieved is slightly lower than adults with 224 μg/L in children 0.6-5 years and after 3 days dosing and 383 μg/L in children 6-15 years. The t_½ of 36 hours in the older children was within the expected range for adults.
Toxicology: Preclinical Safety Data: In high-dose animal studies, giving active substance concentrations 40 fold higher than those expected in clinical practice, azithromycin has been noted to cause reversible phospholipidosis, generally without discernible toxicological consequences. There is no evidence that this is of relevance to the normal use of Azithromycin monohydrate (Zenith) in humans.
Carcinogenic potential: Long-term studies in animals have not been performed to evaluate carcinogenic potential.
Mutagenic potential: Azithromycin monohydrate (Zenith) has shown no mutagenic potential in standard laboratory tests: mouse lymphoma assay, human lymphocyte clastogenic assay and mouse bone marrow clastogenic assay.
Reproductive Toxicity: No teratogenic effects were observed in animal studies of embryotoxicity in mice and rats. In rats, azithromycin dosages of 100 and 200 mg/kg body weight/day led to mild retardations in fetal ossification and in maternal weight gain. In peri-/postnatal studies in rats, mild retardations following treatment with ≥50 mg/kg/day azithromycin were observed.

Azithromycin monohydrate (Zenith) can be applied in situations where micro-organisms sensitive to azithromycin have caused: upper respiratory tract infections: sinusitis, pharyngitis, tonsillitis (see Precautions); acute otitis media; lower respiratory tract infections: acute bronchitis and mild to moderately severe community acquired pneumonia; skin and soft tissue infections; uncomplicated Chlamydia trachomatis urethritis and cervicitis (Precautions).
Considerations should be given to official guidance on the appropriate use of antibacterial agents.

Adults: In uncomplicated Chlamydia trachomatis urethritis and cervicitis the dosage is 1000 mg as a single oral dose.
For all other indications the dosage is 1500 mg, to be administered as 500 mg per day for three consecutive days. Alternatively the same total dosage (1500 mg) can also be given over a period of 5 days with 500 mg on the first day and then 250 mg on days 2  to 5.
Elderly: In the elderly the same dosage as for adults can be given.
Children and adolescents (<18 years): The total dosage in children aged 1 year and older is 30 mg/kg administered as 10 mg/kg once daily for three days, or over a period of five days starting with a single dose of 10 mg/kg on the first day, followed by doses of 5 mg/kg per day for the following 4 days, according to the tables shown as follows. There is limited data on use in children younger than 1 year.
Azithromycin monohydrate (Zenith) 200 mg/5 ml powder for oral suspension: See Table 2.

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The dosage for the treatment of pharyngitis caused by Streptococcus pyogenes is an exception: in the treatment of pharyngitis caused by Streptococcus pyogenes Azithromycin monohydrate (Zenith) has proved to be effective when it is administered to children as a single dose of 10 mg/kg or 20 mg/kg for 3 days with a maximum daily dosage of 500 mg. At these two dosages a comparable clinical effect was observed, even if the eradication of the bacteria was more significant at a daily dosage of 20 mg/kg.
Penicillin is however the drug of first choice in the treatment of pharyngitis caused by Streptococcus pyogenes and the prevention of subsequent rheumatic fever.
Patients with renal insufficiency: In patients with mild to moderate renal insufficiency (creatinine clearance > 40 mL/min) adjustment of the dosage is not necessary. For patients with more serious renal insufficiency: see Precautions.
Patients with hepatic insufficiency: See Precautions.
Method of administration: Before use, the powder should be reconstituted with water: see preparation of the suspension. After reconstitution the drug can be administered using a PE/PP syringe for oral use.
After taking the suspension a bitter after-taste can be avoided by drinking fruit juice directly after swallowing. Azithromycin monohydrate (Zenith) powder for oral suspension should be given in a single daily dosage. The suspension can be taken together with food.

Adverse events experienced in higher than recommended doses were similar to those seen at normal doses. Characteristic symptoms of an overdose of macrolide antibiotics were reversible hearing loss, severe nausea, vomiting and diarrhea. In case of an overdose, lavage and general supporting measures are indicated.

The use of Azithromycin monohydrate (Zenith) is contraindicated in patients with hypersensitivity to azithromycin, to other macrolide antibiotics, or to any of the excipients (see Precautions).

Rare serious allergic reactions, including angioneurotic edema and anaphylaxis (rarely fatal), have been reported. Some of these reactions with azithromycin have resulted in recurrent symptoms and required a longer period of observation and treatment.
Observation for signs of superinfection with non-susceptible organisms, including fungi, is recommended.
Pseudomembranous colitis has been reported with the use of macrolide antibiotics. This diagnosis should therefore be considered in patients who get diarrhea after starting the treatment with Azithromycin monohydrate (Zenith). Should pseudomembranous colitis be induced by azithromycin, then anti-peristaltics should be contraindicated.
There is no experience regarding the safety and efficacy of the long-term application of Azithromycin monohydrate (Zenith) for the previously mentioned indications. In case of quickly recurring infections, treatment with another antibacterial agent should be considered.
Due to the theoretical possibility of ergotism, Azithromycin monohydrate (Zenith)and ergot derivatives should not be co-administered (see Interactions).
Prolonged cardiac repolarization and QT interval, imparting a risk of developing cardiac arrhythmia and torsades de pointes, have been seen in treatment with other macrolides. A similar effect with azithromycin cannot be completely ruled out in patients at increased risk for prolonged cardiac repolarization. Therefore, azithromycin should not be used: in patients with congenital or documented acquired QT prolongation; with other active substances that prolong QT interval such as antiarrhythmics of classes IA and III, cisapride and terfenadine; electrolyte disturbance, particularly in cases of hypokalemia and hypomagnesemia; in [patients with clinically relevant bradycardia, cardiac arrhythmia or severe cardiac insufficiency.
Azithromycin monohydrate (Zenith) is not the substance of first choice for the treatment of pharyngitis and tonsillitis caused by Streptococcus pyogenes. For this and for the prophylaxis of acute rheumatic fever, penicillin is the treatment of first choice.
In case of sexually transmitted diseases, a concomitant infection by T. pallidum should be excluded.
Use in renal impairment: No dose adjustment is necessary in patients with mild to moderate renal impairment (GFR 10-80 mL/min). Caution is advised in patients with severe renal impairment (GFR <10 mL/min) as systemic exposure may be increased (see Pharmacokinetics under Actions).
Use in hepatic impairment: Since Azithromycin monohydrate (Zenith) is metabolized in the liver and excreted in the bile, the medicinal product should not be given to patients suffering from severe liver disease. No studies have been conducted regarding the treatment of such patients with Azithromycin monohydrate (Zenith). When severe liver impairment occurs, the treatment with azithromycin should be ceased.
Azithromycin monohydrate (Zenith) should be administered with caution to patients with neurological or psychiatric disorders.
Azithromycin monohydrate (Zenith) is not indicated for the treatment of infected burn wounds.
Azithromycin monohydrate (Zenith) powder for oral solution is not suitable for treatment of severe infections where a high concentration of the antibiotic in the blood is rapidly needed.
Patients with rare congenital abnormalities such as fructose intolerance, glucose-galactose malabsorption syndrome or sucrase-isomaltase insufficiency should not use this medicinal product.
Effects on the Ability to Drive and Use Machines: No studies on the effects on the ability to drive and use machines have been performed. However, the possibility of undesirable effects like dizziness and convulsions should be taken into account when performing these activities.

Pregnancy: There are no adequate and well controlled studies in pregnant women. Animal reproduction studies show passage across the placenta. No teratogenic effects were observed in rat reproduction studies (see Pharmacology: Toxicology: Preclinical Safety Data under Actions). The safety of Azithromycin monohydrate (Zenith) has not been confirmed with regard to the use of the active substance during pregnancy. Therefore Azithromycin monohydrate (Zenith) should only be used in life threatening cases during pregnancy.
Lactation: Azithromycin monohydrate (Zenith) passes into breast milk. Because it is not known whether Azithromycin monohydrate (Zenith) may have adverse effects on the breast-fed infant, nursing should be discontinued during treatment with Azithromycin monohydrate (Zenith). Among other things, diarrhea, fungi infection of the mucus membrane as well as sensitization is possible in the nursed infant. It is recommended to discard the milk during treatment and up until 2 days after discontinuation of treatment. Nursing may be resumed thereafter.

In this section undesirable effects are defined as follows: Very common (>1/10); common (>1/100, <1/10); uncommon (>1/1000, <1/100); rare (>1/10,000, <1/1000); very rare (<1/10,000), including isolated reports.
Approximately 13% of the patients in clinical trials reported undesirable effects. Undesirable gastrointestinal effects were most common, approximately 10%.
Infections and infestations: Uncommon: Vaginitis. Rare: Candidiasis.
Blood and the lymphatic system disorders: Rare: Thrombocytopenia, hemolytic anemia. Transient mild reductions in neutrophil counts have occasionally been observed in clinical trials for which a causal relationship with azithromycin treatment has not been confirmed.
Immune system disorders: Rare: Anaphylaxis, including edema (rarely fatal) (see Precautions).
Metabolism and nutrition disorders: Uncommon: Anorexia.
Psychiatric disorders: Rare: Aggressive reaction, agitation, anxiety, nervousness, depersonalization, in elderly patients delirium may occur.
Nervous system disorders: Uncommon: Dizziness/vertigo, convulsions, headache, somnolence, disturbances of smell and/or taste. Rare: Paresthesia, syncope, insomnia, hyperactivity.
Ear and labyrinth disorders: Rare: Impaired hearing. Impaired hearing including deafness and/or tinnitus has been reported after prolonged treatment at high doses in clinical trials. A majority of these cases has been reversible, of those that were possible to follow up.
Cardiac disorders: Rare: Palpitations, arrhythmia (including ventricular tachycardia). There is a potential risk of QT prolongation and torsades de pointes, particularly in patients who are susceptible to these conditions.
Gastrointestinal disorders: Common: Nausea, diarrhea, abdominal discomfort (pain/cramps), vomiting. Uncommon: Loose stools (as a result of infrequent dehydration), flatulence, dyspepsia. Rare: Constipation, pseudomembranous colitis, pancreatitis, discoloration of the teeth, tongue discoloration.
Hepatobiliary disorders: Rare: Abnormal liver function test values, hepatitis, cholestatic jaundice, rare cases of hepatic necrosis and hepatic failure which have rarely resulted in death.
Skin and subcutaneous tissue disorders: Uncommon: Rash, pruritus. Rare: Angioneurotic edema, urticaria, photosensitivity, erythema multiforme, Stevens-Johnson's syndrome, toxic epidermal necrolysis.
Musculoskeletal connective tissue and bone disorders: Uncommon: Arthralgia.
Renal and urinary disorders: Rare: Interstitial nephritis, acute renal failure.
General disorders: Rare: Asthenia, fatigue, malaise.

Theophylline: Pharmacokinetic studies in healthy volunteers revealed no interaction between azithromycin and theophylline with concomitant administration. Since interactions of other macrolides with theophylline were reported, care should be taken of signs of increased theophylline levels.
Coumarin-type oral anticoagulants: An increased tendency of hemorrhage has been reported in connection with the concurrent use of Azithromycin monohydrate (Zenith) and warfarin or coumarin-like oral anticoagulants. Attention should be paid to the frequency of prothrombin time monitoring.
Carbamazepine: In a pharmacokinetic interaction study in healthy volunteers, no significant effect was seen in the pharmacokinetics of carbamazepine or its active metabolite.
Ergotamine derivatives: In patients treated with ergotamine derivatives, ergotism can be induced by the concomitant administration of some macrolide antibiotics. There is no known data about the possibility of an interaction between ergotamine derivatives and Azithromycin monohydrate (Zenith). Because of the theoretical possibility of ergotism, Azithromycin monohydrate (Zenith) and ergotamine derivatives should not be combined.
Cyclosporine: Since pharmacokinetic and clinical studies on the possible combined effects of Azithromycin monohydrate (Zenith) and cyclosporine have not been carried out, the therapeutic situation should be carefully considered before these active substances are administered simultaneously. If combination treatment is considered justifiable, the cyclosporine levels should be carefully monitored and the dosage should be adjusted accordingly.
Digoxin: It is known that some macrolide antibiotics limit the metabolism of digoxin (in the gut). In patients treated concomitantly with Azithromycin monohydrate (Zenith) and digoxin, the possibility of increased digoxin levels should be borne in mind, and digoxin levels monitored.
Antacids: In a pharmacokinetic study on the effect of concomitant administration of antacids and Azithromycin monohydrate (Zenith), no effect on the total bioavailability was seen, although the peak serum levels were reduced by 30%. Azithromycin monohydrate (Zenith) should be taken at least 1 hours before or 2 hours after the antacid.
Trimethoprim/Sulfamethoxazole: Coadministration of trimethoprim/sulfamethoxazole (160 mg/800 mg) for 7 days with Azithromycin monohydrate (Zenith) 1200 mg on day 7 had no significant effect on peak concentrations, total exposure or urinary excretion of either trimethoprim or sulfamethoxazole. Azithromycin monohydrate (Zenith) serum concentrations were similar to those seen in other studies.
Fluconazole: Coadministration of a single dose of 1200 mg Azithromycin monohydrate (Zenith) did not alter the pharmacokinetics of a single dose of 800 mg fluconazole. Total exposure and t_½ of azithromycin monohydrate were unchanged by the co-administration of fluconazole, however, a clinically insignificant decrease in C_max (18%) of azithromycin monohydrate was observed.
Zidovudine: Single administrations of 1000 mg of Azithromycin monohydrate (Zenith) and multiple administrations of 600 or 1200 mg Azithromycin monohydrate (Zenith) had no effect on the plasma pharmacokinetics or the renal excretion of zidovudine or its glucuronide metabolite. However, administration of Azithromycin monohydrate (Zenith) increased the concentrations of phosphorylated zidovudine, the clinically active metabolite, in peripheral blood mononuclear cells. The clinical significance of this finding is unclear, but it may be of benefit to patients.
Terfenadine: Azithromycin monohydrate (Zenith) has no effect on the pharmacokinetics of terfenadine administered every 12 hours in the recommended dosage of 60 mg. Measured in a steady-state dosing of terfenadine, adding Azithromycin monohydrate (Zenith) did not result in a significant change in the cardiac repolarization (QT interval).
Cisapride: Cisapride is metabolized in the liver by the enzyme CYP3A4. Because macrolides inhibit this enzyme, concomitant administration of cisapride may cause the increase of QT interval prolongation, ventricular arrhythmias and Torsades de pointes.
Didanosine: In comparison to placebo, daily doses of 1200 mg azithromycin monohydrate and didanosine did not seem to have an effect on the pharmacokinetics of didanosine in the 6 test subjects.
Rifabutin: Coadministration of Azithromycin monohydrate (Zenith) and rifabutin did not affect the serum concentrations of either active substance. Neutropenia was observed in subjects receiving concomitant treatment of Azithromycin monohydrate (Zenith) and rifabutin.
Although neutropenia has been associated with the use of rifabutin, a causal relationship to combination with Azithromycin monohydrate (Zenith) has not been established.
Astemizole, Triazolam, Midazolam, Alfentanil: There is no known data regarding interaction with astemizole, triazolam, midazolam or alfentanil. Caution is needed in the concomitant use of these medicinal products and Azithromycin monohydrate (Zenith), as an increase of action with the concomitant use of the macrolide antibiotic erythromycin has been described.
Indinavir: Coadministration of a single dose of 1200 mg Azithromycin monohydrate (Zenith) had no statistically significant effect on the pharmacokinetics of indinavir administered as 800 mg 3 times daily for 5 days.
Nelfinavir: Concomitant administration of 1200 mg Azithromycin monohydrate (Zenith) and steady-state nelfinavir (750 mg 3 times daily) resulted in an average 16% decrease of nelfinavir AUC, an increase of Azithromycin monohydrate (Zenith) AUC and C_max with 113% and 136%, respectively. No dose adjustment is necessary but patients should be monitored for known side effects of Azithromycin monohydrate (Zenith).

Incompatibilities: Not applicable.
Preparation of the suspension: Shake the dry powder loose. Add the amount of water described as follows to the powder.
Azithromycin monohydrate (Zenith) 200 mg/5 mL: For 20 mL (800 mg) bottle: add 10 mL water.
Shake well until a homogenous suspension is achieved. For administration, the syringe adapter should be placed in the neck of the bottle and the stopper should be opened.

Store at temperatures not exceeding 30°C.
Reconstituted suspension: Do not store above 25°C.
Do not refrigerate or freeze. The ready-to-use suspension is stable for 5 days.

Macrolides

J01FA10 - azithromycin ; Belongs to the class of macrolides. Used in the systemic treatment of infections.

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