Af Kit

Uses

Azithromycin is used for infections caused by susceptible organisms in-

Upper respiratory tract infections including sinusitis, pharyngitis and tonsillitis

Lower respiratory tract infections including bronchitis, acute bacterial exacerbations of chronic obstructive pulmonary

disease (COPD)

Otitis media

Skin and soft tissue infections including cellulitis, pyoderma, erysipelas, wound infections

Diarrhea, Shigellosis

Sexually transmitted diseases, especially in the treatment of non-gonococcal urethritis and cervicitis due to Chlamydia trachomatis

Genital ulcer disease in men due to Haemophilus ducreyi (chancroid)

Mild or moderate typhoid due to multiple-antibacterial resistant organisms

Prophylaxis against a-hemolytic (viridans group) streptococcal bacterial endocarditis

Other infections including odontogenic infections, bartonella infections, toxoplasmosis, babesiosis

For the treatment of fungal corneal ulcers/ keratitis.

Ornidazole is used for Amoebiasis (Intestinal and hepatic), Giardiasis, Trichomoniasis, Bacterial vaginosis, Treatment of susceptible anaerobic infections

Af Kit is also used to associated treatment for these conditions: Acute Bacterial Sinusitis (ABS), Acute Otitis Media, Acute bacterial exacerbation of COPD caused by Haemophilus Influenza Infections, Moraxella Catarrhalis Infection, Streptococcus Pneumoniae Infections, Bacterial Conjunctivitis, Bacterial Sinusitis, Cervicitis, Chancroid, Community Acquired Pneumonia (CAP), Genital Ulcer Disease (GUD), Pelvic Inflammatory Disease (PID), Pharyngitis, Streptococcal Pharyngitis, Streptococcal tonsillitis, Tonsillitis bacterial, Traveler's Diarrhea, Uncomplicated Skin and Skin Structure Infections, UrethritisCandida intertrigo, Candida pneumonia, Candida urinary tract infection, Candidemia, Candidiasis, Coccidioidomycosis, Esophageal Candidiasis, Fungal peritonitis caused by Candida, Infections, Fungal, Meningitis, Cryptococcal, Oropharyngeal Candidiasis, Peritoneal candidiasis, Pneumonia cryptococcal, Pruritus, Skin Irritation, Systemic Candida Infections caused by Candida, Vaginal Candidiasis, Disseminated CandidiasisAmebiasis, Anaerobic Bacterial Infection, Chlamydial Infections, Gastrointestinal Infections caused by entamoeba histolytica, Giardiasis, Mixed Vaginal Infections, Surgical Site Infections, Trichomonal Vaginitis, Trichomoniasis

How Af Kit works

In order to replicate, bacteria require a specific process of protein synthesis, enabled by ribosomal proteins . Azithromycin binds to the 23S rRNA of the bacterial 50S ribosomal subunit. It stops bacterial protein synthesis by inhibiting the transpeptidation/translocation step of protein synthesis and by inhibiting the assembly of the 50S ribosomal subunit , . This results in the control of various bacterial infections , . The strong affinity of macrolides, including azithromycin, for bacterial ribosomes, is consistent with their broad‐spectrum antibacterial activities .

Azithromycin is highly stable at a low pH, giving it a longer serum half-life and increasing its concentrations in tissues compared to erythromycin .

Fluconazole is a very selective inhibitor of fungal cytochrome P450 dependent enzyme lanosterol 14-α-demethylase. This enzyme normally works to convert lanosterol to ergosterol, which is necessary for fungal cell wall synthesis. The free nitrogen atom located on the azole ring of fluconazole binds with a single iron atom located in the heme group of lanosterol 14-α-demethylase. This prevents oxygen activation and, as a result, inhibits the demethylation of lanosterol, halting the process of ergosterol biosynthesis. Methylated sterols are then found to accumulate in the fungal cellular membrane, leading to an arrest of fungal growth. These accumulated sterols negatively affect the structure and function of the fungal cell plasma membrane.

Fluconazole resistance may arise from an alteration in the amount or function of the target enzyme (lanosterol 14-α-demethylase), altered access to this enzyme, or a combination of the above. Other mechanisms may also be implicated, and studies are ongoing.

Dosage

Af Kit dosage

Azithromycin tablet can be taken with or without food. Azithromycin suspension should be taken at least 1 hour before or 2 hours after meal.

Oral:

Adult:

For respiratory tract infections, otitis media and skin & soft tissue infections: 500 mg once daily for 3 days or an alternative to this as 500 mg once on day 1, followed by 250 mg once daily for next 4 days. For sexually transmitted diseases like genital ulcer, non-gonococcal urethritis and cervicitis due to Chlamydia trachomatis : a single 1 gm (1000 mg) dose. For the treatment of urethritis and cervicitis due to Neisseria gonorrhoeae : a single 2 gm (2000 mg) dose. In typhoid, 500 mg once daily for 7 days. In Cholera, a single 1 gm (1000 mg) dose. In Shigellosis, 500 mg once on day 1, followed by 250 mg once daily for next 4 days.

Instill 1 drop to be instilled into the affected eye(s) 5 times daily.

Amoebiasis:

• Adults: 500 mg twice a day for 5 days.
• Children: 10-25 mg per kg body weight in two divided doses.

Amoebic dysentery:

• Adults: 1.5 gm once a day for 3 days.
• Children: 40 mg per kg body weight, once a day for 3 days.

Giardiasis:

• Adults: 1.5 gm once daily for 1-2 days.
• Children: 40 mg per kg body weight for 2 days.

Trichomoniasis: 1.5 gm once or 500 mg twice a day for 5 days. Sexual partner should also be treated at the same time.

Bacterial vaginosis: 3 tablets of 500 mg each as a single dose or one tablet of 500 mg once daily for 5-7 days.

Azithromycin can be taken with or without food.

To reconstitute Azithromycin 15 ml powder for suspension: Add 10 ml or 2 tea spoonfuls of just boiled and cooled water to the content of the bottle and shake well to mix uniformly.

To reconstitute Azithromycin 30 ml powder for suspension: Add 20 ml or 4 tea spoonfuls of just boiled and cooled water to the content of the bottle and shake well to mix uniformly.

To reconstitute Azithromycin 50 ml powder for suspension: Add 35 ml or 7 tea spoonfuls of just boiled and cooled water to the content of the bottle and shake well to mix uniformly.

Side Effects

Azithromycin is well tolerated with a low incidence of side efects. The side effects include nausea, vomiting, abdominal discomfort (pain/cramps), flatulence, diarrhea, headache, dizziness, and skin rashes and are reversible upon discontinuation of therapy. Reversible elevations in liver transaminases have been observed occasionally. Transient mild reductions in neutrophil counts have occasionally been observed in clinical trials, although causal relationship to Azithromycin has not been established.

This drug is generally well tolerated. Eosinophillia has been reported in some patients.

Side effects of Ornidazole have been mainly limited to the gastrointestinal tract (nausea, vomiting, epigastric pain) and central nervous system (dizziness, headache, lassitude). Unlike other nitroimidazoles, Ornidazole does not interact with alcohol, although this requires further study.

Leukopenia has been described occasionally during therapy. Adverse central nervous system (CNS) effects of Ornidazole have mainly included headache, dizziness, lassitude or somnolence, fatigue and weakness. Adverse CNS effects of Ornidazole may be less than that happens with metronidazole. Seizures have not been reported with Ornidazole in studies available to date.

Toxicity

Rat Oral LD50: >2000 mk/kg

Possible major adverse effects include cardiovascular arrhythmias and hearing loss. Macrolide resistance is also an ongoing issue. Hepatotoxicity has been observed in rare cases.

A note on the risk of liver toxicity:

Due to the act that azithromycin is mainly eliminated by the liver, caution should be observed when azithromycin is given to patients with decreased hepatic function .

A note on potential renal toxicity:

Because limited data in patients with renal GFR Label.

Use in Pregnancy:

This drug is categorized as a pregnancy category B drug. Reproduction studies have been done in rats and mice at doses up to moderately maternally toxic doses (for example, 200 mg/kg/day). These doses, based on a mg/m2 basis, are approximately 4 and 2 times, respectively, the human daily dose of 500 mg. In the animal studies, no harmful effects to the fetus due to azithromycin were observed. There are, at this time, no conclusive and well-controlled studies that have been done in pregnant women. Because animal reproduction studies do not always predict human response, azithromycin should be used during pregnancy only if clearly needed .

Nursing Mothers:

It is unknown at this time whether azithromycin is excreted in human milk. Because many other drugs are excreted in human milk, caution should be observed when azithromycin is given to a nursing woman .

Carcinogenesis, Mutagenesis, Impairment of Fertility:

Long-term studies in animals have not been performed to study carcinogenic potential. Azithromycin has demonstrated no potential to be mutagenic in standard laboratory tests. No evidence of negative effects on fertility due to azithromycin was found .

Acute oral toxicity (LD50): 1271 mg/kg (rat)

Overdose information

Fluconazole overdoses have been associated with hallucination and paranoia, sometimes in combination. In cases of overdose, employ supportive treatment. Gastric lavage may be necessary. Other modalities such as forced diuresis or hemodialysis may also be used.

A note on liver toxicity

The FDA label warns that this drug carries a risk of hepatotoxicity. Rare but serious cases of serious hepatic toxicity have been reported, especially in patients with serious underlying medical conditions using fluconazole. This group of patients has an increased risk of fatality when using fluconazole. In patients with existing liver dysfunction, use caution during fluconazole therapy. Those who are found to have abnormal liver function tests during therapy should be carefully monitored for the development of increasingly severe injury to the liver. Fluconazole should be stopped if its use is likely to be the underlying cause of liver injury, and medical attention should be sought. Fluconazole induced hepatotoxicity is usually reversible.

Carcinogenesis, mutagenesis, and impairment of fertility

Fluconazole demonstrated no evidence of carcinogenic risk in mice and rats treated orally for 24 months at doses equivalent to approximately 2-7 time the recommended human dose). Male rats given fluconazole at doses equivalent to supratherapeutic human doses showed an increased incidence of hepatocellular adenomas. Cytogenetic studies in vivo and in vitro demonstrated no sign of chromosomal mutation. The significance of these findings for humans is unknown.

Use in pregnancy

There are no sufficient and well-controlled studies of fluconazole use in pregnant women. Available human data do not show an increased risk of congenital anomalies after pregnant women were treated with standard doses (27 Several case reports describe rare but striking congenital anomalies observed in infants who were exposed to fluconazole at high doses reaching 400-800 mg/day, primarily in the first trimester of pregnancy. Similar findings were observed in animal studies. If this drug is administered during pregnancy, or if the patient becomes pregnant while taking fluconazole, the risk should be discussed thoroughly.

Use in nursing

Fluconazole is secreted in breastmilk at high concentrations. Exercise caution if this drug is used during nursing.

Precaution

As with any antibiotic, observation for signs of super infection with non-susceptable organisms, including fungi, is recommended. Precaution should be taken in patients with more severe renal impairment.

Use of fluconazole may result in overgrowth of non-susceptible strains of candida other than Candida albicans

In patient with ataxia, vertigo, and mental confusion, Ornidazole should be prescribed with caution. During prolonged treatment with Ornidazole, blood dyscrasia namely mild leukopenia have been reported rarely. In case leukopenia occurs, the decision to discontinue the therapy should depend upon the gravity of infection.

Interaction

Antacids: Peak serum levels but not the total extent of absorption are reduced by aluminium and magnesium containing antacids in the stomach. Azithromycin should therefore be taken at least 1 hour before or 2 hours after taking these antacids.

Ergot Derivatives: Because of the theoretical possibility of ergotism, concomitant administration of ergot derivatives and Azithromycin should be avoided. Digoxin & Cyclosporin: Macrolides have been known to increase the plasma concentration of Digoxin & Cyclosporin and so caution should be exercised while co-administration is necessary.

Anti-Histamines: A potentially life threatening interaction between erythromycin and terfenadine or astemizole have been reported. Although such an interaction with Azithromycin is not established yet, it is wise to avoid concomitant use of Azithromycin and terfenadine or astemizole.

Fluconazole can alter pharmacokinetics of certain drugs undergoing hepatic metabolism.

Like other imidazoles, Ornidazole has a mild potential to cause disulfiramlike reactions. Concomitant administration of oral anticoagulants may increase the risk of haemorrhage due to diminished hepatic metabolism. Ornidazole has been reported to decrease the clearance of 5-fluorouracil.

Volume of Distribution

After oral administration, azithromycin is widely distributed in tissues with an apparent steady-state volume of distribution of 31.1 L/kg . Significantly greater azithromycin concentrations have been measured in the tissues rather than in plasma or serum , . The lung, tonsils and prostate are organs have shown a particularly high rate of azithromycin uptake .

This drug is concentrated within macrophages and polymorphonucleocytes, allowing for effective activity against Chlamydia trachomatis . In addition, azithromycin is found to be concentrated in phagocytes and fibroblasts, shown by in vitro incubation techniques. In vivo studies demonstrate that concentration in phagocytes may contribute to azithromycin distribution to inflamed tissues .

The apparent volume of distribution is said to be similar to the volume of distribution of total body water. One clinical study of healthy volunteers administered 50 mg/kg of fluconazole was 39L, based on a body weight of 60kg.

Fluconazole shows substantial penetration in many body fluids, which is a property that renders it an ideal treatment for systemic fungal infections, especially when administered over a longer time. Fluconazole is found in high concentrations in the stratum corneum and dermis-epidermis of skin, in addition to eccrine sweat. Fluconazole is found to accumulate especially well in the stratum corneum, which is beneficial in superficial fungal infections.[L6496] Saliva and sputum concentrations of fluconazole are found to be similar to the plasma concentrations. In patients diagnosed with fungal meningitis, fluconazole CSF (cerebrospinal fluid) levels are measured to be about 80% of the corresponding plasma levels. Therefore, fluconazole crosses the blood-brain barrier[L6496]. The meninges are increasingly permeable to fluconazole in states of inflammation, facilitating treatment in meningitis.

Elimination Route

Bioavailability of azithromycin is 37% following oral administration. Absorption is not affected by food. Macrolide absorption in the intestines is believed to be mediated by P-glycoprotein (ABCB1) efflux transporters, which are known to be encoded by the ABCB1 gene .

The pharmacokinetic properties of fluconazole are comparable after administration by the intravenous (IV) and oral (PO) routes. In healthy volunteers, the bioavailability of orally administered fluconazole is measured to be above 90%. It is extensively absorbed in the gastrointestinal tract when an oral dose is taken. Oral absorption is not affected by food intake with fluconazole but may increase the time until the maximum concentration is reached.

Tmax (or the time taken to achieve the maximum concentration) in one clinical study of healthy patients receiving 50 mg/kg of fluconazole was 3 hours.

Peak plasma concentrations (Cmax) in fasting and healthy volunteers occur between 1-2 hours post-dose. Steady-state concentrations are achieved within 5 to 10 days after oral doses of 50-400 mg administered once daily. Administration of a loading dose on the first day of fluconazole treatment, or twice the usual daily dose, leads to plasma concentrations close to steady-state by the second day. Mean AUC (area under the curve) was 20.3 in healthy volunteers receiving 25 mg of fluconazole.

A note on the capsule and powder form and malabsorption syndromes

The capsule forms of fluconazole often contain lactose and should not be administered with hereditary galactose intolerance, Lapp lactase enzyme deficiency, or malabsorption of glucose/galactose. The powder form, used for the oral suspension, lists sucrose as an ingredient and should not be used in patients who have been diagnosed with fructose, glucose/galactose malabsorption, and sucrase-isomaltase enzyme deficiency.

Half Life

Terminal elimination half-life: 68 hours

The terminal elimination half-life in the plasma is approximately 30 hours (range: 20-50 hours) after oral administration. The long plasma elimination half-life supports a single dose therapy for vaginal candidiasis, once daily and once weekly dosing for other indications.[L6496]. Patients with renal failure may require dosage adjustment, and half-life can be significantly increased in these patients.

Clearance

Mean apparent plasma cl=630 mL/min (following single 500 mg oral and i.v. dose)

This drug is mainly eliminated by the kidneys and the mean body clearance in adults is reported to be 0.23 mL/min/kg. One clinical study of healthy subjects showed total clearance of 19.5 ± 4.7 mL/min and renal clearance of 14.7 ± 3.7 mL/min (1.17 ± 0.28 and 0.88 ± 0.22 L/h).

Clearance in the pediatric population varies according to age, as does clearance in patients with renal failure.

Elimination Route

Biliary excretion of azithromycin, primarily as unchanged drug, is a major route of elimination. Over a 1 week period, approximately 6% of the administered dose is found as unchanged drug in urine .

In normal volunteers, fluconazole is cleared primarily by renal excretion, with approximately 80% of the administered dose measured in the urine as unchanged drug. About 11% of the dose is excreted in the urine as metabolites.. A study of a 50mg radiolabeled dose of fluconazole revealed that 93.3% of the dose was found excreted in the urine.

A note on renal failure

The pharmacokinetics of fluconazole are significantly affected by renal dysfunction. The dose of fluconazole may need to be reduced in patients with decreased renal function. A 3-hour hemodialysis treatment lowers plasma fluconazole concentrations by about 50%.

Pregnancy & Breastfeeding use

Pregnancy: US FDA pregnancy category B. In the animal studies, no evidence of harm to the fetus due to Azithromycin was found. Because animal reproduction studies are not always predictive of human response, Azithromycin should be used during pregnancy only if clearly needed.

Lactation: It is not known whether Azithromycin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Azithromycin is administered to nursing mother.

Use in pregnancy: Pregnancy category C. There are no adequate and well-controlled studies in pregnant women. Fluconazole should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Use in lactation: Nursing mother should not be given as the drug is excreted in breast milk in concentration similar to plasma.

Adequate clinical trials have not been conducted. Ornidazole should be prescribed only if the potential benefit justifies the potential risk to fetus/neonate.

Contraindication

Azithromycin is contraindicated in patients hypersensitive to Azithromycin or any other macrolide antibiotic. Co-administration of ergot derivatives and Azithromycin is contraindicated. Azithromycin is contraindicated in patients with hepatic diseases.

The drug is contraindicated in patients with hypersensitivity to azoles.

Previous hypersensitivity to Ornidazole and to other nitroimidazoles. Ornidazole is contraindicated in central nervous system disorders, particularly in epilepsy or in peripheral neuropathy.

Special Warning

Pediatric Use: Azithromycin oral dosage forms can be administered to pediatric patients from 6 months of age. Safety and effectiveness of azithromycin for injection in children or adolescents under 16 years have not been established.

Acute Overdose

There are no data available on overdose with Azithromycin. Typical symptoms of overdosage with macrolide antibiotics include hearing loss, severe nausea, vomiting and diarrhoea. Gastric lavage and general supportive measures are indicated.

Renal Impairment Haemodialysis patients: Give a supplemental dose (50% of the usual dose) before dialysis.

Hepatic Impairment Severe: Double the interval between doses.

Storage Condition

Azithromycin IV infusion: When diluted according to the instructions, azithromycin for injection is stable for 24 hours at or below room temperature 30° C, or for 7 days if stored under refrigeration 5° C.

Azithromycin capsule, tablet and dry powder for suspension: should be stored at room temperature (below 30° C). Any unused portion of reconstituted Azithromycin suspension should be discarded after 5 days.

Azithromycin eye drops: Store unopened bottle under refrigeration at 2°C to 8°C. Once the bottle is opened, store at 2°C to 25°C for up to 14 days. Discard after the 14 days.

Keep out of the reach of children. Store in a cool, dry place, away from heat and direct light. Do not use more than 4 weeks after opening the bottle

Store at room temperature and protect from light and moisture.

Innovators Monograph

You find simplified version here Af Kit