MAGITRO 400

Indications:

Prophylaxis and treatment of infections in which anaerobic bacteria have been identified or are suspected to be the cause.

Magitro 400 is active against a wide range of pathogenic micro-organisms notably species of Bacteroides, Fusobacteria, Clostridia, Eubacteria, anaerobic cocci, Gardnerella vaginalis and Trichomonas, Entamoeba histolytica, Giardia lamblia, Balantidium coli.

Magitro 400 is indicated in adults and children for the following indications:

• The prevention of post-operative infections due to anaerobic bacteria (species of Bacteroidesand streptococci).
• The treatment of septicaemia, bacteraemia, peritonitis, brain abscess, necrotising pneumonia, osteomyelitis, puerperal sepsis, pelvic abscess, pelvic cellulitis, and post-operative wound infections from which pathogenic anaerobes have been isolated.
• Urogenital trichomoniasis in the female (Trichomonal vaginitis) and in the male.
• Bacterial vaginosis (also known as non-specific vaginitis, anaerobic vaginosis or Gardnerella vaginitis).
• All forms of amoebiasis (intestinal and extra-intestinal disease, symptomless cyst passers).
• Acute ulcerative gingivitis.
• Anaerobically-infected leg ulcers and pressure sores.
• Acute dental infections (e.g. acute pericoronitis and acute apical infections).

Considerations should be given to official guidance on the appropriate use of antibacterial agents.

Administration, dosage:

Administration: To be taken with water, no chewing during or after meal.

Dosage:

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

Adults: 400 mg 8 hourly over the 24 hours immediately preceding the operation followed by post-operative intravenous or rectal administration until the patient is able to take tablets.

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

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

Anaerobic infections: Treatment duration with metronidazole is approximately 7 days depending on the severity of infection and the patient’s clinical response.

Treatment of established anaerobic infection:

Adults: 800 mg followed by 400 mg 8 hourly.

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

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

Newborns with a gestation age < 40 weeks, accumulation of metronidazole can occur during the first week of life, therefore the concentrations of metronidazole in serum should preferable be monitored after a few day therapy.

Protozoal and other infections:

Dosage
	Duration of dosage in days	Adults and children over 10 years		Children
				7 – 10 years	3 – 7 years		1 – 3 years
Trichomoniasis Alternatively, sexual partner should be treated.	7 or	2 g as a single dose or 200 mg 3 times daily or		40 mg/kg orally as a single or 15-30 mg/kg/day divided in 2 – 3 doses; not to exceed 2 g/dose
	5-7	400 mg twice daily
Bacterial vaginosis	5-7 or	400 mg twice daily
	1	2 g as a single  dose
Amoebiasis (a) Invasive intestinal disease in susceptible subjects	5	800 mg three times daily		400 mg three times daily	200 mg four times daily		200 mg three times daily
(b) Intestinal disease in less susceptible subjects and chronic amoebic hepatitis	5-10	400 mg three times daily		200 mg three times daily	100 mg four times daily		100 mg three times daily
(c) Amoebic liver abscess also other forms of extra-intestinal amoebiasis	5	400 mg three times daily		200 mg three times daily	100 mg four times daily		100 mg three times daily
(d) Symptomless cyst passers	5-10	400-800 mg three times daily		200–400 mg three times daily	100-200 mg four times daily		100 – 200 mg three times daily
	Alternatively, doses may be expressed by body weight: 35 – 50 mg/kg daily in 3 divided doses for 5 – 10 days, not to exceed 2.4 g/day
Giardiasis	3	2 g once daily or		1 g once daily	600-800 mg once daily		500 mg once daily
	5	400 mg three times daily or
	7- 10	500 mg twice daily
	Alternatively, as expressed in mg per kg of body weight: 15 – 40 mg/kg/day divided in 2 – 3 doses.
Acute ulcerative gingivitis	3		200 mg three times daily	100 mg three times daily		100 mg twice times daily		50 mg three times daily
Acute dental infections	3-7		200 mg three times daily
Leg ulcers and pressure sores	7		400 mg three times daily
Children and infants <10 kg should receive proportionally smaller dosages. Elderly: Magitro 400 is well tolerated but caution should be exercised when using high doses.

Eradication of Helicobacter pylori in paediatric patients:

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

Some special attention on the handling of the medicine before and after use:

There are no special requirements for handling the drug after use.

Contraindications:

Hypersensitivity to nitroimidazole, metronidazole or to any of excipients of this medicine.

Warnings and precautions for use:

Regular clinical and laboratory monitoring (especially leukocyte count) is required if magitro 400 is indicated for more than 10 days and patients should be monitored for adverse reactions such as peripheral or central neuropathy (such as paresthesia, ataxia, vertigo, convulsive disorder).

Metronidazole should be indicated with caution in patients with severe and chronic central and peripheral nervous system disease due to the risk of neurologic symptom exacerbation.

Cases of severe hepatotoxicity/acute liver impairment, including fatals with rapid onset after initation of therapy in patients with Cockayne syndrome have been reported with systemic metronidazole-containing products. Therefore, for such patients, metronidazole should be indicated after careful risk-benefit assessment and only when no alternative treatment is available. Liver function tests should be performed right before initiating, during and after the end of treatment until liver function is within normal range or until baseline values are reached. If liver function tests are significantly increased during treatment, the drug should be discontinued.

Patients with Cockayne syndrome should immediately inform any symptoms of potential liver damage to physician and discontinue metronidazole.

Cases of severe skin reaction such as Stevens Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) or acute generalised exanthematous pustulosis (AGEP) syndrome have been reported with metronidazole. If symptoms or signs of SJS, TEN or AGEP occur, treatment must be discontinued immediately.

It is possible that after Trichomonas vaginalis is eliminated, gonococcal infection is still existing.

Half-life of metronidazole is unchanged in presence of renal impairment. Therefore, dose reduction of metronidazole is not necessary. However, such patients retain metabolites of metronidazole. Its clinical significance is currently unknown.

In hemodialysis patients, metronidazole and its metabolites are effectively eliminated during the 8-hour hemodialysis period. Therefore, metronidazole should be reindicated immediately after hemodialysis.

No dose adjustment is required in patients with renal impairment undergoing intermittent peritoneal dialysis (IDP) or continuous ambulatory peritoneal dialysis (CAPD).

Metronidazole is metabolized mainly by oxidation in liver. Significant impairment of metronidazole clearance may occur in cases of progressive liver impairment. Significant accumulation may occur in patients with hepatic encephalopathy, and high plasma concentrations of metronidazole may contribute to symptoms of encephalopathy. Therefore, Magitro should be indicated with caution to patients with hepatic encephalopathy. Daily dose should be reduced to ¹/₃ and may be taken once daily.

Patients should be warned that Magitro darken urine.

Because there is insufficient evidence of mutagenicity in humans, long-term use of the drug should be carefully considered.

This medication contains dyes (Sunset yellow lake and Tartrazine dye) which may cause allergic reactions.

Pregnancy and lactation:

There has been no sufficient study of metronidazole safety during pregnancy, but it has been widely used for many years without obvious side effects. However, like other drugs, magitro 400 should not be indicated during pregnancy or lactation unless considered necessary by physician; in these cases, short-term treatment, high dose is not recommended.

Effects on ability to drive, use machines:

Patients should be warned about possibility of drowsiness, dizziness, confusion, hallucinations, convulsions or transient visual disturbances and advised not to drive or operate machinery if these symptoms occur.

Interactions, incompatibilities of medicine:

Interaction of the drug with other drugs and other types of interactions:

Patients should not drink alcohol during metronidazole therapy and for at least 48 hours afterwards because of potential for a disulfiram-type reaction (antabuse effect). Psychotic reactions have been reported in patients taking concomitant metronidazole and disulfiram.

Some ancoagulants effects have been reported when metronidazole is indicated with oral warfarin-type anticoagulant. Dose may be required reduction later. Prothrombin time should be monitored. There is no interaction with heparin.

Evidence of renal damage has been reported in patients treated concomitantly with lithium and metronidazole. Lithium treatment should be tapered or discontinued prior to metronidazole administration. Lithium, creatinine and electrolyte concentrations should be monitored in patients treated with lithium while taking metronidazole.

Concomitant administration of metronidazole and phenobarbital or phenytoin increases the metabolism of metronidazole to much higher rate than normal, elimination half-life being reduced to about 3 hours.

Metronidazole reduces 5-fluorouracil clearance and may therefore increase 5-fluorouracil toxicity.

Patients taking ciclosporin are at risk of increased serum ciclosporin concentration. Close monitoring of ciclosporin and serum creatinine is recommended when co-administered.

Busulfan plasma concentration may be increased by metronidazole, can lead to severe busulfan toxicity

Incompatibilities:

Because there are no studies of drug incompatibility, do not mix this drug with other drugs.

Undesirable effects:

Side effects are classified according to frequency: Very common (ADR ≥ 1/10), common (1/100 ≤ ADR < 1/10), uncommon (1/1,000 ≤ ADR < 1/100), rare (1/10,000 ≤ ADR < 1/1,000), very rare (ADR < 1/10,000); can not be estimated from the available data “Not known”.

Organ system	Undesirable effects
Blood and lymphatic system disorders
Very rare	Agranulocytosis, neutropenia, thrombocytopenia, pancytopenia
Not known	Leukopenia
Immune system disorders
Rare	Anaphylaxis
Not known	Angioedema, urticaria, fever
Metabolic and nutritional disorders
Not known	Anorexia
Psychiatric disorders
Very rare	Psychiatric disorders, including confusion and hallucinations
Not known	Depressed mood
Nervous system disorder
Very rare	Encephalopathy (confusing, fever, headache, hallucinations, paralysis, sensitivity to light, visual and movement disorder, stiff neck) and subacute cerebellar syndrome (ataxia, dyskinesia, asthenia, vibration, tremor), drowsiness, dizziness, headache, convulsions
Not known	During intensive and/or prolonged metronidazole therapy, peripheral sensory neuropathy or transient epileptic seizures. In most cases, neuropathy disappeared after therapy discontinuation or dosage decrease. Aseptic meningitis
Eye disorders
Very rare	Visual disorders (diplopia and transient myopia)
Not known	Optic neuropathy/neuritis
Ear and labyrinth disorders
Not known	Hearing impairment/hearing loss, tinnitus
Gastrointestinal disorders
Not known	Taste disturbance, oral mucositis, tongue discoloration, nausea, vomiting, gastrointestinal disturbances such as epigastric pain and diarrhea
Hepatobiliary disorders
Very rare	Elevated liver enzymes (AST, ALT, alkaline phosphatase), cholestatic or mixed hepatitis and hepatocellular injury, jaundice and pancreatitis are reversible upon discontinuation of the drug Cases of liver impairment requiring liver transplantation have been reported in patients treated with metronidazole in combination with other antibiotics
Skin and subcutaneous tissue disorders
Very rare	Skin rash, pustular rash, acute generalized pustular syndrome, pruritus, flushing
Not known	Erythema multiforme, Stevens-Johnson syndrome or toxic epidermal necrolysis, fixed pigmented erythema
Musculoskeletal and connective tissue disorders
Very rare	Muscle pain, joint pain
Renal and urinary disorders
Very rare	Dark urine

Inform your doctor or pharmacist of any undesirable effects occured while taking the drug.

Overdose and management:

Overdose: Single doses of metronidazole, up to 12 g, have been reported in suicidality and accidental overdose. Symptoms include vomiting, ataxia, and mild disorientation.

Management: There is no specific antidote. In case of suspected overdose, treatment should be symptomatic and supportive.

Pharmacodynamics:

Pharmacological group: Systemic antibiotics and antiparasitic drugs.

ATC code: J01XD01, P01AB01.

Metronidazole is active against protozoa and bacteria, effective against Trichomonas vaginalis and other protozoa including Entamoeba histolytica and Giardia lamblia and against anaerobic bacteria.

Pharmacokinetics:

Metronidazole is rapidly and almost completely absorbed; peak plasma concentration is reached after 20 minutes to 3 hours. Half-life of metronidazole is 8.5 ± 2.9 hours.

Metronidazole can be used in chronic renal impairment; it is rapidly eliminated from plasma by hemodialysis. Metronidazole is excreted in milk but in infants lactated by mothers taking normal dose will be significantly less than those lactated by mothers receiving therapeutic infant dose.