Benznidazole - Indications, Contraindications, Warnings, and Precautions

Overview:

Benznidazole falls under the category of antimicrobials, where the disease-causing microbes will get destroyed by the drug's action. Benznidazole is the hallmark drug that fights against the Chagas disease, typically for younger population groups. The use of Benznidazole for Chagas disease is endorsed by the United States drug regulatory body - the Food and Drug Administration (FDA). Though it is primarily employed for the younger population, it is also effective for the adult population, who are in the initial stages of Chagas disease.

How Does Benznidazole Work?

Benznidazole is a drug that comes under the specific antiprotozoal drug class. These medications check parasitic infections like Chagas disease by hampering the manufacturing of genetic material like deoxyribonucleic acids and ribonucleic acids. The effect of Benznidazole is further enhanced when it is acted upon by the parasitic enzyme, which then breaks down the drug molecules into active compounds. It is these active compounds that target the genetic material and other proteins in the parasitic body. It has an extended antimicrobial activity that focuses the parasites in all the growth stages.

Uses:

Benznidazole is routinely employed for dealing with Chagas disease, specifically for patients under the age category two to twelve. However, recent studies concluded its effectiveness in the adult population with uncomplicated Chagas disease. However, Benznidazole is not fruitful for other microbial infections.

Available Doses and Dosage Forms:

Benznidazole is marketed in pill form under varying dosages. For small children who cannot swallow the pill form, the slurry form of Benznidazole is prepared out of the tablet using water as the medium to dissolve the tablet. The dosage of the drug is determined by considering the age, body weight, and severity of the parasitic infection.

• Available Doses: 12.5 milligrams (mg) and 100 mg.

• Dosage Forms: Tablet form.

Warnings:

• Genotoxicity: Certain animal studies, as well as human studies, have concluded the ability of Benznidazole to precipitate alterations in the genetic makeup. Benznidazole enhances the probability of developing genetic alteration by almost two times.

• Carcinogenicity: Benznidazole is also reported to be carcinogenic in animals like rodents. Long-term intake of Benznidazole carries the risk of developing certain cancerous changes in the cells. However, there is no conclusive evidence on humans. Hence, its use is restricted to indicated cases.

• Harm to Fetus: Benznidazole should never be given to a pregnant woman as it holds the risk of harming the developing child in the womb. Animal trials using Benznidazole precipitated severe malformations (defective formations) of vital organs in the fetus (child in the womb). Hence, it is strictly advised to confirm the pregnancy status before initiating therapy using Benznidazole.

• Skin Allergies: Benznidazole is known to cause severe allergic reactions in the skin. The exaggerated reaction to the drug gives rise to skin issues like exfoliative dermatitis (the outermost skin layer undergoes peeling and flaking), eczema (desiccated and flaky skin), and other rashes over the skin surface. At times, it could end up in severe fatal skin reactions like toxic epidermal necrolysis (skin layer undergoes extensive destruction and flaking) and toxic pustuloderma (red-colored rashes poke up all over the skin surface).

• Altered Blood Cell Counts: Benznidazole suppresses the formation of blood cells in the bone marrow, which eventually precipitates a significant drop in red blood cells, white blood cells, and platelet counts.

• Neurological Troubles: Benznidazole intake induces the development of numbness in certain parts of the body, which persists for months. The numbness arises due to its effect on the peripheral nerves. Severe nerve involvement often entails the withdrawal of Benznidazole.

For Patients:

What Is Chagas Disease?

Chagas disease is a potentially dangerous infection that is induced by a specific category of parasites called Trypanosoma cruzi. American trypanosomiasis is the widely used synonym for Chagas disease, as its occurrence is restricted primarily within America. Trypanosoma cruzi are parasites that routinely reside and colonize in insects like triatomine bugs (blood-sucking insects); from those bugs, the parasite transmits into animals and human beings. Parasites will be shredded through the excretory material (feces) of the infected bugs. Once the person gets exposed to the bug feces, the parasites enter the person’s body through wound or skin abrasions. In addition, Chagas disease can also be acquired through organ transplantation and blood transfusion.

Furthermore, these parasites can cross the placental barrier (protective covering enclosing the baby in the womb) and can transmit the infection from the mother’s body to the child in the womb. The manifestations of Chagas disease vary from person to person. However, it routinely exhibits two stages - acute and chronic phase. The acute phase elicits general symptoms like fever, weakness, vomiting, loose stool, body pain, and skin rashes. The asymptomatic acute phase is also reported rarely, where the person does not experience any symptoms. The acute phase itself poses complications in individuals with remarkably compromised immunity. The extended phase is the chronic phase, where the affected person develops troubles in the intestines and grave complications in the heart.

When and Why Is Benznidazole Prescribed?

Benznidazole is an extensively employed medicine for the treatment of a parasitic infection called Chagas disease. Its effectiveness in tackling the Chagas disease has been proven for the age category of two to twelve years. It is not advised for pediatric patients younger than two years because of the lack of supportive evidence regarding the safety of the medicine in that particular age group. However, adult patients also gain benefits from Benznidazole for dealing with Chagas disease in the acute stage without considerable complications. If Chagas disease is not treated promptly, it could precipitate grave complications and even risk one’s life.

Things to Inform the Doctor Before Taking Benznidazole:

It is mandatory that the patient should reveal all health-related information to the doctors in order to ensure safety during Benznidazole therapy. Some of the relevant information to be shared with the doctor includes the following:

• If the person ever had a history of exaggerated allergic responses towards Benznidazole or related medicines like Metronidazole or towards any of the components in these drugs, it should be properly communicated with the doctor before initiating the therapy.

• Information regarding the undergoing treatment and medication should be disclosed to make sure that undesirable drug-drug interactions do not happen. Interactions may, at times, hamper the effectiveness of the drugs and impact the health negatively.

• Other underlying disease conditions need to be assessed before prescribing Benznidazole. Hence, it is strictly instructed to provide all the details of other ailments that the person suffers, particularly liver diseases and blood-related issues. The previous history of disease conditions also needs to be disclosed to determine the possibility of complications.

• If the person is either pregnant or planning for conception in the near future, the doctor should be made aware of that. Intake of Benznidazole during pregnancy is toxic to the developing baby.

• Breastfeeding mothers should inform their doctors regarding lactation because Benznidazole can reach the child’s body through breast milk and bring about undesired effects on the child’s body.

• Alcoholic drinks interfere with Benznidazole and precipitate various issues like indigestion, stomach pain, and exaggerated sweating. Hence, patients should disclose the habit of drinking alcoholic beverages before the start of treatment.

Things to Consider While Taking Benznidazole:

While undergoing therapy using Benznidazole, patients should be cautious about certain things.

• Benznidazole is capable of precipitating side effects and unwanted reactions in the body. Therefore, in the event of an allergic reaction, the patients are instructed to withdraw the drug immediately and seek medical assistance.

• If the person gets pregnant while on Benznidazole therapy, immediately report it to the doctor.

• Benznidazole can bring about anemia (collapsed red cell count), so while undergoing treatment using this drug; one should always look for signs of anemia, like weakness and paleness.

• Before taking the pills, make sure that the pills are within the usage period. If not, those pills are not suitable for consumption.

What Are the Instructions to Be Followed While on Benznidazole?

• Patients should consume only the required dose of Benznidazole, which is prescribed by the doctor. The dose is determined by considering the body weight; hence, self-administration without consulting a doctor can end up with either an inadequate dose or an exaggerated dose.

• Dose modification or stoppage of the medicine without a doctor’s consultation is strictly not encouraged.

• With the commencement of Benznidazole therapy, the person should refrain from alcohol consumption. Alcohol and Benznidazole interact with each other and precipitate other health issues like indigestion and many more.

• Effective contraceptive measures should be initiated while on Benznidazole therapy to check unintentional conception during the treatment period.

What Are the Possible Side Effects of Benznidazole?

• Benznidazole can bring about grave side effects like carcinogenesis (ability to instigate cancer development) and genotoxicity (harming the genes). It can trigger alterations in the gene sequence and can lead to genetic disorders.

• Toxic skin reactions are other major side effects of Benznidazole. In addition, it also gives rise to numbness and other neurological troubles in the patient in the long run.

• Skin rashes, skin flaking, pigmented spots over the skin, and tingling and prickling sensations are occasionally encountered with Benznidazole intake.

• Fever and bulged lymph nodes are also noted with Benznidazole therapy. Certain patients reported having a burning kind of feeling in the extremities, like legs and hands.

• Less severe side effects like weakness, tremors, stomach upset, headache, vertigo, and belly pain are frequently experienced by the person undergoing treatment with Benznidazole. There will be a significant compromise in hunger, which in turn reflects in weight loss.

What Should Be Done if a Dose Is Missed?

Benznidazole is advised to be taken two times a day. If, by chance, the person fails to take the dose at the instructed time, it is recommended to take the pill immediately after realizing the missed dose. However, if it is close to the next scheduled dose, there is no need to take the missed dose. It is instructed to move ahead with the subsequent dose without considering the missed one. Never administer two pills to compromise the missed one, as it carries the risk of toxicity.

How to Treat Benznidazole Overdose?

Benznidazole overdose should be treated cautiously. If the person develops serious reactions like strained breathing and collapse, it necessitates immediate medical attention. There is no single medicine that is known to counteract the effects of Benznidazole. The emergency room or the Center for Poison Control should be contacted immediately to speed up the treatment.

How to Store Benznidazole?

• Benznidazole pills are routinely marketed in pill bottles. The pills should be stored in the bottle itself till consumption.

• Both high temperature and cold temperatures alter the chemical composition of the pills; hence, it is advised to be kept under room temperature within the range of 20 to 25 degrees Celsius. Never expose the tablets to freezing temperatures.

• Always keep the bottle lid firmly closed to check the incidental intake of pills by small kids.

For Doctors:

Indications:

Benznidazole is indicated for:

• Chagas disease in pediatric patients (within two to twelve years).

What Are the Contraindications of Benznidazole?

Benznidazole can be prescribed only after considering the health status, concurrent medications, and underlying disease condition. Potential contraindications for Benznidazole include the following:

• A history of exaggerated reactions towards Benznidazole or its constituents is a grave contraindication for Benznidazole. Subsequent intake of the medicine can precipitate anaphylactic reactions.

• Concurrent intake of Benznidazole with Disulfiram brings about psychotic reactions, and hence, it is contraindicated. So, patients who have consumed Disulfiram can start Benznidazole treatment only after two weeks of Disulfiram withdrawal.

• Propylene glycol-containing beverages and other alcoholic drinks exhibit considerable interaction with Benznidazole and precipitate Disulfiram-like reactions.

Dosage and Administration:

• Dosage: The dosage of Benznidazole is determined according to the individual’s body weight. Five milligrams (mg) per kilogram (kg) of body weight to eight mg per kg of body weight is the dosage regime for younger patients within two to twelve years in a day. The entire dose is then given in two divided doses.

• Route of Administration: Benznidazole should be taken through the oral route, either in pill form or in slurry form, by dissolving the pill in water.

Pharmacology:

1. Mechanism of Action:

When Benznidazole is administered to a person infected with the Trypanosoma cruzi parasite, the drug molecule gets acted by nitroreductase enzymes in the parasite. These enzymes reduce the Benznidazole into electrophilic and highly active metabolites. These electrophilic molecules then attach with the parasitic genetic materials, lipids, and proteins and induce harm to these molecules. Thereby, it brings about genetic damage to the parasitic cells, and eventually, the organism will die. In this way, Benznidazole works to kill the causative agent and tackle the disease. It belongs to the class of nitroimidazole drugs.

2. Pharmacodynamics:

Benznidazole also influences the expression of certain other genes like TcPGP1, TcPGP2, TcCyP19, and TcFSOD-A. However, reliable data are unavailable to provide conclusive evidence.

3. Pharmacokinetics:

• Absorption: The utmost concentration of Benznidazole is attained after 3.2 hours and two hours when taken along with food and under fasting, respectively. However, the maximum concentration remains unaltered even with food interaction.

• Distribution: Benzonidazole is largely distributed with the help of plasma proteins. These drug molecules attach with the plasma protein and form complexes, which are then distributed throughout the body.

• Metabolism: Liver enzyme cytochrome P 450 is responsible for the metabolism of Benznidazole in the human body, while in Trypanosoma cruzi, it gets reduced by the parasitic enzyme nitroreductase.

• Elimination: Removal of Benznidazole and its metabolites happens primarily through the urinary route, while a smaller proportion is removed via the fecal route.

What Are the Drug Interactions of Benznidazole?

Benznidazole elicits interactions with certain other drugs and brings unpleasant effects on the body.

• Simultaneous intake of Disulfiram and Benznidazole is strictly not advised as these drugs interact with each other and precipitate psychotic reactions. There should at least be a gap of two weeks between Disulfiram withdrawal and Benznidazole therapy initiation.

• Propylene glycol and alcohol elicit structural resemblance to Benznidazole; hence, it is advised not to take these products while undergoing therapy using Benznidazole.

Warnings and Precautions Before Prescribing Benznidazole:

• Carcinogenicity and Genotoxicity: Recent research has proven the ability of Benznidazole to induce mutations in human cells. It has been concluded that Benznidazole can cause carcinogenesis in animal cells.

• Toxic to Fetus: The intake of Benznidazole by a pregnant lady poses risks to the fetus to develop inborn malformations. Hence, the possibility of pregnancy should be checked by advising appropriate contraceptive measures.

• Hypersensitivity Reactions: Benznidazole can trigger hypersensitivity reactions in the form of grave skin diseases like toxic epidermal necrolysis, eosinophilic drug reactions, and generalized exanthematous pustulosis. It is strongly instructed to withdraw the drug intake in the event of hypersensitivity reactions and to get medical help at the earliest.

• Blood-Related Discrepancies: Benznidazole suppresses bone marrow activities and precipitates anemia, neutropenia, leukopenia, and thrombocytopenia. Hence, a thorough assessment of the blood profile should be made for the patients under Benznidazole therapy to enhance the early detection of discrepancies.

• Neurological Issues: Peripheral neuropathy and paresthesia are the potential neurological issues that arise following Benznidazole therapy. Neurological troubles necessitate immediate stoppage of the offending drug’s intake.

• Infertility: Animal studies have revealed that Benznidazole can impair and compromise the fertility of males. However, there is not much data available regarding the extent and nature of the impairment.

Other Specifications:

• Benznidazole During Pregnancy: Benznidazole is specifically not advised in pregnant women and also in women who are planning for conception. Benznidazole therapy will be initiated only after ruling out the pregnancy status and advising appropriate birth control measures to check unplanned conceptions.

• Benznidazole During Breastfeeding: Breastfeeding is not advised while undergoing therapy using Benznidazole. Certain studies concluded that the drug gets into the breastmilk when administered to a lactating mother, which can pose health implications for the breastfed child.