Source: Health Products Regulatory Authority (ZA) Revision Year: 2022 Publisher: Fresenius Kabi Manufacturing SA (Pty) Ltd, 6 Gibaud Road, Korsten, Port Elizabeth 6020, South Africa
Clinical and laboratory monitoring is advised in patients receiving Trichazole for more than 10 days. This period may only be exceeded in individual cases after a very strict benefit-risk assessment. Only in the rarest possible case should the treatment be repeated. Limiting the duration of treatment is necessary because damage to human germ cells cannot be excluded. Intensive or prolonged Trichazole therapy should be conducted only under conditions of close surveillance for clinical and biological effects and under specialist direction. Prolonged or intensive treatment with Trichazole has been associated with peripheral neuropathy, transient epileptiform seizures and leukopenia.
In case of prolonged treatment, occurrence of undesirable effects such as paraesthesia, ataxia, dizziness and convulsive crises should be checked. High dose regimes have been associated with transient epileptiform seizures.
Pseudomembranous colitis has been reported following the use of Trichazole.
The half-life of metronidazole is reported to be longer in neonates and in patients with severe hepatic impairment; that of the hydroxyl metabolite is prolonged in patients with substantial renal impairment (see section 5.2).
Caution is needed in patients with severe hepatic impairment. The dose of Trichazole should be reduced as necessary. Trichazole is mainly metabolised by hepatic oxidation. Substantial impairment of metronidazole clearance may occur in the presence of advanced hepatic insufficiency. The risk/benefit ratio of using Trichazole to treat trichomoniasis in such patients should be carefully considered. Plasma levels of metronidazole should be closely monitored. Caution is needed in patients with hepatic encephalopathy. Patients with severe hepatic encephalopathy metabolise metronidazole slowly, with resultant accumulation of metronidazole. This may cause exacerbation of CNS adverse effects. The dose of Trichazole should be reduced as necessary.
Cases of severe hepatotoxicity/acute hepatic failure, including cases with a fatal outcome with very rapid onset after treatment initiation in patients with Cockayne syndrome have been reported with products containing metronidazole for systemic use, such as Trichazole. In this population, Trichazole should therefore be used after careful benefit-risk assessment and only if no alternative treatment is available. Liver function tests must be performed just prior to the start of therapy, throughout and after end of treatment until liver function is within normal ranges, or until the baseline values are reached. If the liver function tests become markedly elevated during treatment, Trichazole should be discontinued.
Patients with Cockayne syndrome should be advised to immediately report any symptoms of potential liver injury to their physician and stop using Trichazole.
Trichazole is removed during haemodialysis and should be administered after the procedure is finished.
Patients with renal impairment, including patients receiving peritoneal dialysis, should be monitored for signs of toxicity due to the potential accumulation of toxic metronidazole metabolites.
Patients should be advised not to drink alcohol before, during Trichazole therapy and for at least one day and up to 3 days afterwards because of the possibility of a disulfiram-like reaction (see see section 4.5).
Co-administration with busulfan: as plasma level of busulfan may be increased significantly, it may lead to severe busulfan toxicity and death.
Studies have shown Trichazole to be mutagenic in bacteria and carcinogenic in some animals. Trichazole should be administered with caution to patients with hepatic encephalopathy.
Trichazole has anti-treponemal activity and may mask the immunological response seen in untreated early syphilis; contacts of patients with syphilis receiving Trichazole should probably be screened for an additional 4–8 weeks.
Patients should be warned that Trichazole may darken the urine (due to metronidazole metabolite).
Due to increased risk for adverse reactions, regular clinical and laboratory monitoring (including blood count) are advised in cases of high-dose, prolonged or repeated treatment, in case of antecedents of blood dyscrasia, in case of severe infection and in severe hepatic insufficiency.
Trichazole contains sodium. This may be harmful to patients on a low sodium diet.
Acute psychoses or confusion have been associated with the concomitant use of Trichazole and disulfiram.
When given in conjunction with alcohol, Trichazole may provoke a disulfiram-like reaction in some individuals (effects including intense vasodilation and flushing on the face and neck, restlessness, anxiety, tachycardia, tachypnoea, headache, nausea, vomiting, hyperpnoea, chest pains, sweating, pallor and hypotension). Reactions have occurred after the administration of medicines formulated with alcohol, including injections as well as after drinking alcohol. Alcoholic beverages and medicines containing alcohol should not be consumed during therapy and for at least 1–3 days afterwards (see section 4.4).
Potentiation of the anticoagulant effect and increased haemorrhagic risk. In case of coadministration with warfarin, prothrombin time/INR should be more frequently monitored and warfarin therapy/dose adjusted during treatment with Trichazole.
Plasma levels of lithium may be increased by Trichazole. Plasma concentration of lithium, creatinine and electrolytes should be monitored in patients under treatment with lithium while they receive Trichazole.
Risk of elevation of ciclosporin serum levels. Serum ciclosporin and serum creatinine should be closely monitored when co-administration is necessary.
There is evidence that phenytoin might accelerate the metabolism of Trichazole. Plasma concentrations of Trichazole are decreased by the concomitant administration of phenobarbital, with a consequent reduction in the effectiveness of Trichazole.
Reduced clearance of 5-flourouracil resulting in increased toxicity of 5-fluorouracil may occur.
Plasma levels of busulfan may be increased by Trichazole, which may lead to severe busulfan toxicity and death (see section 4.3, and section 4.4).
Hepatic metabolism may be decreased when Trichazole and cimetidine are used concurrently, possibly resulting in delayed elimination and increased serum metronidazole concentrations with an increased risk of neurological side effects.
Trichazole can potentialise the effects of vecuronium.
Cholestyramine may delay or reduce the absorption of Trichazole.
Concomitant use of Trichazole and CYP3A4 substrates (e.g., amiodarone, tacrolimus, cyclosporine, carbamazepine, and quinidine) may increase respective CYP3A4-substrate plasma levels. Monitoring of plasma concentrations of CYP3A4 substrates may be necessary.
Trichazole may immobilise treponema and thus may lead to falsely positive Nelson’s test. Trichazole may interfere with serum aspartate transaminase (AST), alanine transaminase (ALT), lactate dehydrogenase (LDH), triglycerides, and glucose hexokinase determinations. Metronidazole causes an increase in ultraviolet absorbance at 340 nm resulting in falsely decreased values.
Safety and efficacy in pregnancy and lactation have not been established.
Trichazole crosses the placenta barrier and is excreted in breastmilk.
Trichazole should not be used during pregnancy and women breastfeeding their infants.
Patients should be warned about the potential for confusion, dizziness, hallucinations, convulsions or transient visual disorders, and advised not to drive or operate machinery if these symptoms occur.
The following side effects have been reported.
Less frequent: Leukopenia, agranulocytosis, pancytopenia, neutropenia, thrombocytopenia.
Frequency unknown: Eosinophilia.
Less frequent: Anaphylaxis, anaphylactic shock, Jarisch-Herxheimer reaction, angioedema.
Frequency unknown: Hypersensitivity.
Frequency unknown: Anorexia, decreased appetite.
Less frequent: Psychotic disorders including confusion, irritability and hallucinations, changes in mood or mental state such as depression or confusion.
Frequency unknown: Vertigo.
Frequent: Dysgeusia.
Less frequent: Weakness, dizziness, drowsiness, insomnia, headache. Reports of encephalopathy (e.g. confusion) and subacute cerebellar syndrome (e.g. ataxia, dysarthria, gait impairment, nystagmus and tremor), which may resolve with discontinuation of the medicine, aseptic meningitis, ataxia, dysarthria. Peripheral neuropathy, usually presenting as numbness or tingling in the extremities, and epileptic form seizures are serious adverse effects on the nervous system that have been associated especially with high doses of Trichazole or prolonged treatment.
Frequency unknown: Paraesthesia, hypoaesthesia.
Less frequent: The occurrence of transient vision disorder such as diplopia and myopia may follow the use of Trichazole, optic neuropathy.
Thrombophlebitis may follow intravenous administration of Trichazole.
Frequency unknown: Tachycardia, palpitations.
Frequency unknown: Nasal congestion, dyspnoea.
Frequent: Gastrointestinal discomfort, especially nausea and taste disorders; nausea is sometimes accompanied by headache, and vomiting. Diarrhoea, dry mouth, a furred tongue, oral mucositis, stomatitis, glossitis and constipation.
Less frequent: Antibiotic-associated colitis, pancreatitis, upper abdominal pain, tongue discolouration.
Frequency unknown: Pseudomembranous colitis, coated tongue and unpleasant taste.
Less frequent: Reversible abnormal liver function and cholestatic hepatitis, sometimes with jaundice.
Frequency unknown: Raised liver enzyme values.
Less frequent: Pustular eruptions, mild erythematous eruptions with fleeting joint pains resembling serum sickness, Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme.
Frequency unknown: Skin rash, fever, flushing, pruritus, face swelling, urticaria, hyperhidrosis.
Frequent: Myalgia.
Frequency unknown: Muscle spasms, arthralgia.
Less frequent: Urethral discomfort and darkening of the urine may occur.
Frequency unknown: Dysuria.
Less frequent: Asthenia, mucosal inflammation, pyrexia.
Frequency unknown: Injection site reaction, malaise, facial oedema, peripheral oedema, chest pain, chills.
Reporting suspected adverse reactions after authorisation of Trichazole is important. It allows continued monitoring of the benefit/risk balance of Trichazole. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the “6.04 Adverse Drug Reactions Reporting Form”, found online under SAHPRA’s publications: https://www.sahpra.org.za/Publications/Index/8.
This medicine must not be mixed with other medicines except those mentioned in section 6.6.
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