STATIZOL- oral Suspension: Each 5 mL contains Metronidazole (Benzoate) 200mg.

 

The selective action of this compound against anaerobes and anoxic and hypoxic cells is due to the mode of action. This produces biochemical lesions in the cells, thus causing death. The major site of action is believed to be DNA, where it causes loss of the helical structure and inhibits synthesis.

 

It is readily absorbed from the gastro-intestinal tract and widely distributed in body tissues. Half-life in plasma is about 8-10 hours. About 10% is bound to plasma proteins.

It penetrates well into body tissues and fluids, including vaginal secretions, seminal fluid, saliva and breast milk. Therapeutic concentrations are also achieved in cerebrospinal fluid.

Unchanged metronidazole and several metabolites are excreted in the urine, the liver is the main site of metabolism and the major metabolites are as a result of side chain oxidation, forming glucuronides.

Preclinical safety data:

Metronidazole has been shown to be carcinogenic in the mouse and in the rat following chronic oral administration however similar studies in the hamster have given negative results. Epidemiological studies have provided no clear evidence of an increased carcinogenic risk in humans.

 

-Metronidazole is indicated in the prophylaxis and treatment of infections in which anaerobic bacteria have been identified or are suspected as the pathogen.

-Metronidazole is active against a wide range of pathogenic micro-organisms, notably Trichomonas vaginalis, Entamoeba histolytica, Giardia lamblia, Balantidium coli and other species of bacteroides, fusobacteria, eubacteria, clostridia and anaerobic cocci.

-It is indicated in Adults, Children and Newborns with a gestation age of over 40 weeks for:

1-The treatment of septicaemia, bacteraemia, brain abscess, necrotising pneumonia, osteomyelitis, puerperal sepsis, pelvic abscess, pelvic cellulitis, peritonitis and post-operative wound infections from which one or more pathogenic anaerobes have been isolated.

2-The prevention of post-operative infections caused by anaerobic bacteria particularly species of bacteroides and anaerobic streptococci.

-Adults and Children over 10 years only for:

1-Bacterial vaginosis (also known as non-specific vaginitis, anaerobic vaginitis or Gardnerella vaginitis).

2-Acute dental infections (e.g. acute pericoronitis and acute apical infections).

3-Anaerobically infected leg ulcers and pressure sores.

-Adults and Children for:

1-The treatment of urogenital trichomoniasis in the female (trichomonal vaginitis) and in the male.

2-All forms of amoebiasis (intestinal and extra-intestinal disease and that of symptomless cyst passers)

3-Giardiasis

4-Acute ulcerative gingivitis.

Children for : Eradication of Helicobacter pylori

 

Known hypersensitivity to Metronidazole and/or hydroxybenzoates.

 

Frequency, type and severity of adverse reactions in children are the same as in adults.

clinicians who contemplate continuous therapy for the relief of chronic conditions, for periods longer than those recommended are advised to consider the possible therapeutic benefit against the risk of peripheral neuropathy.

Very rare: agranulocytosis, neutropenia, thrombocytopenia and pancytopenia, often reversible on drug withdrawal, although fatalities have occurred.

Not known: A moderate leucopenia has been reported in some patients but the white cell count has always returned to normal before or after treatment has been completed.

Rare: Anaphylaxis.

Not known: urticaria, angioedema and fever

Not known: anorexia.

Very rare: psychotic disorders, including confusion and hallucinations.

Not known: depressed mood.

Very rare: Encephalopathy (eg. confusion, fever, headache, hallucinations, paralysis, and light sensitivity, disturbances in sight and movement, stiff neck) and subacute cerebellar syndrome (eg. ataxia, dysathria, gait impairment, nystagmus and tremor) have been reported very rarely which may resolve on discontinuation of the drug, Drowsiness, dizziness, convulsions, headache, ataxia, inco-ordination of movement.

Not known: During intensive and/or prolonged metronidazole therapy a few instances of peripheral neuropathy or transient epileptiform seizures have been reported. In most cases neuropathy disappeared after treatment was stopped or when dosage was reduced, Aseptic meningitis has been reported.

Very rare: transient visual disorders such as diplopia and myopia have been reported.

Not known: Optic neuropathy/neuritis has been reported.

Not known: Unpleasant taste in the mouth, oral mucositis, furred tongue, nausea, vomiting, gastro-intestinal disturbances such as epigastric pain and diarrhoea.

Very rare: Abnormal liver function tests, increase in liver enzymes (AST, ALT, alkaline phosphatase), cholestatic or mixed hepatitis, and hepatocellular liver injury, jaundice and pancreatitis, reversible on drug withdrawal have been reported, Cases of liver failure requiring liver transplant have been reported in patients treated with metronidazole in combination with other antibiotic drugs.

Very rare: skin rashes, pustular eruptions, pruritus, flushing.

Not known: Erythema multiforme may occur, which may be reversed on drug withdrawal, Stevens-Johnson syndrome or toxic epidermal necrolysis.

Very rare: myalgia, arthralgia.

Very rare: darkening of the urine (due to metronidazole metabolite)

 

-Regular clinical and laboratory monitoring (especially leucocyte count) are advised if administration of Metronidazole for more than 10 days is considered to be necessary and patients should be monitored for adverse reactions such as peripheral or central neuropathy (such as paraesthesia, ataxia, dizziness, convulsive seizures).

-There is the possibility that after Trichomonas vaginalis has been eliminated a gonococcal infection might persist.

-The elimination half-life of metronidazole remains unchanged in the presence of renal failure. The dosage of metronidazole therefore needs no reduction. Such patients however, retain the metabolites of metronidazole. The clinical significance of this is not known at present.

-In patients undergoing haemodialysis, metronidazole and metabolites are efficiently removed during an eight-hour period of dialysis. Metronidazole should therefore, be re-administered immediately after haemodialysis.

-No routine adjustment in the dosage of Metronidazole need to be made in patients with renal failure undergoing intermittent peritoneal dialysis (IPD) or continuous ambulatory peritoneal dialysis (CAPD).

-Metronidazole is mainly metabolised by hepatic oxidation. Substantial impairment of metronidazole clearance may occur in the presence of advanced hepatic insufficiency.

-Significant cumulation may occur in patients with hepatic encephalopathy and the resulting high plasma concentrations of metronidazole may contribute to the symptoms of encephalopathy.

-Metronidazole should be administered with caution to patients with hepatic encephalopathy. The daily dosage may be reduced to one third and may be administered once daily.

-Metronidazole should be used with caution in patients with active or chronic severe peripheral and central nervous system disease due to the risk of neurological aggravation.

-Methyl, ethyl and propyl hydroxybenzoates are contained in this product which may cause allergic reactions (possibly delayed).

-Patients should be warned that metronidazole may darken urine.

-Due to inadequate evidence on the mutagenicity risk in humans (see section 5.3), the use of Metronidazole for longer treatment than usually required should be carefully considered.

 

-Patients should be advised not to take alcohol during metronidazole therapy and for at least 48 hours afterwards because of the possibility of a disulfiram-like (antabuse effect) reaction. Psychotic reactions have been reported in patients who were using metronidazole and disulfiram concurrently.

-Some potentiation of anticoagulant therapy has been reported when metronidazole has been used with the warfarin type oral anti-coagulants. Dosage of the anticoagulant may require reducing. Prothrombin time should be monitored. No interactions have been reported of the heparin type.

-Lithium retention accompanied by evidence of possible renal damage has been reported in patients treated simultaneously with lithium and metronidazole. Lithium treatment should be tapered or withdrawn before administering metronidazole. Plasma concentration of lithium, creatinine and electrolytes should be monitored in patients under treatment with lithium while they receive metronidazole.

-Patients receiving phenobarbital metabolize metronidazole at a much greater rate than normally, reducing the half-life to approximately three hours.

-Increased serum carbamazepine levels and toxicity have been seen in patients given concomitant metronidazole.

-Aspartate amino transferase assays may give spuriously low values in patients taking metronidazole, depending on the method used.

-Clinicians who contemplate continuous therapy for the relief of chronic conditions, for periods no longer than those recommended, are advised to consider the possible therapeutic benefit against the risk of peripheral neuropathy.

-Metronidazole reduces the clearance of 5-fluorouracil and can therefore result in increased toxicity of 5-fluorouracil.

-Patients receiving ciclosporin or tacrolimus with metronidazole are at risk of elevated ciclosporin / tacrolimus serum levels. Serum ciclosporin / tacrolimus and serum creatinine should be closely monitored when coadministration is necessary.

-Plasma levels of busulfan may be increased by metronidazole which may lead to severe busulfan toxicity.

 

There is inadequate evidence of the safety of metronidazole in pregnancy. Metronidazole should not therefore be given during pregnancy or during lactation unless the physician considers it essential, in these circumstances short, high dosage regimes are not recommended.

A significant amount of metronidazole is found in breast milk and breast feeding should be avoided after a large dose. This could give a bitter taste to the milk.

 

Patients should be warned about the potential for drowsiness, dizziness, confusion, hallucinations, convulsions or transient visual disorders, and advised not to drive or operate machinery if these symptoms occur.

 

1-Prophylaxis: against anaerobic infection- chiefly in the context of abdominal (especially colorectal) and gynaecological surgery.

Dosage: 400mg at 8 hourly intervals during the 24 hours preceding the operation followed by postoperative intravenous or rectal administration until the patient is able to take Metronidazole by mouth.

Children < 12 years: 20 – 30mg/kg as a single dose given 1 – 2 hours before surgery.

Newborns with a gestation age <40 weeks: 10mg/kg body weight as a single dose before operation.

Elderly: Caution is advised in the elderly, particularly at high doses, although there is limited information available on modification of drug.

2-Treatment of established anaerobic infection: 800 mg followed by 400mg at 8 hourly intervals.

Children > 8 weeks to 12 years of age: The usual daily dose is 20 – 30mg/kg/day as a single dose or divided into 7.5mg/kg every 8 hours. The daily dose may be increased to 40mg/kg, depending on the severity of the infection. Duration of treatment is usually 7 days.

Children < 8 weeks of age: 15mg/kg as a single dose daily or divided into 7.5mg/kg every 12 hours.

In newborns with a gestation age <40 weeks: accumulation of metronidazole can occur during the first week of life, which is why the concentrations of metronidazole in serum should preferably be monitored after a few days therapy.

Children and babies weighing less than 10Kg should receive proportionally smaller doses.

Metronidazole is well tolerated by the elderly, but a pharmacokinetic study suggests cautious use of high dosage regimen in this age group.

As a part of combination therapy: 20mg/kg/day not to exceed 500mg twice daily for 7 – 14 days. Official guidelines should be consulted before initiating therapy.

 

Single oral doses of metronidazole, up to 12g have been reported in suicide attempts and accidental overdoses. Symptoms were limited to vomiting, ataxia and slight disorientation. There is no specific antidote for metronidazole overdosage. In cases of suspected massive overdose, symptomatic and supportive treatment should be instituted.

 

STATIZOL- Oral suspension: A carton package of glass bottle of 100 mL.

 

14-STORAGE CONDITIONS:                          

Store STATIZOL- Oral suspension at temperature below 25°C. protect from light