Carbimazole

Carbimazole is an anti-thyroid agent belonging to the pharmacological class of Thyroid Function Modulator.

Carbimazole is FDA-approved for the treatment of hyperthyroidism.

In the intestines, carbimazole is rapidly absorbed, converting into methimazole visible in the blood. It concentrates swiftly in the thyroid, extending carbimazole's activity. Hydrolysis and enzymatic decarboxylation in the blood transform carbimazole into methimazole, undergoing oxidative decomposition in the liver and thyroid, resulting in a 5.3 to 5.4-hour half-life. Over 90% of orally administered carbimazole is eliminated in urine as methimazole or its metabolites.

The most common side effects of Carbimazole are nausea, headache, joint pain, gastrointestinal disturbances, skin rashes, and itching.

Carbimazole is available as a tablet.

The molecule is available in India, Canada, the United Kingdom, Australia, Canada, Germany, France, Italy and Japan.

Carbimazole is an anti-thyroid agent belonging to the pharmacological class of Thyroid Function Modulator.

Prodrug carbimazole is metabolized to thiamazole, also called methimazole, which prevents iodide from being organized and iodothyronine residues from coupling, suppressing thyroid hormone production. Thyroxine and di-iodotyrosine synthesis are inhibited by carbimazole, reducing the thyroid's uptake and concentration of inorganic iodine. After turning methimazole into its active form, the thyroid peroxidase enzyme is prevented from coupling and iodinating the tyrosine residues on thyroglobulin, which reduces the production of the thyroid hormones T3 and T4.

The onset of action for Carbimazole may generally take hours to days for noticeable effects after administration.

Carbimazole's peak plasma concentration (Cmax) occurs approximately one hour after administration.

The time taken to reach the peak plasma concentration (tmax) of Carbimazole is typically within 1 to 2 hours after oral ingestion.

Carbimazole is available as a tablet.

Tablets: To be swallowed whole with water/liquid. Do not chew, crush or break it.

As the physician recommends, take the medication orally twice or thrice daily for adults as directed.

Hyperthyroidism, specifically in Graves' disease.

In Hyperthyroidism

Carbimazole actively diminishes thyroid hormone levels, alleviating symptoms associated with hyperthyroidism, such as palpitations, anxiety, perspiration, shakiness, and heat intolerance. It aims to enhance your overall quality of life by effectively regulating thyroid function and mitigating the disruptive effects of an overactive thyroid gland.

Carbimazole is indicated for hyperthyroidism, particularly in conditions like Graves' disease. It effectively inhibits the overproduction of thyroid hormones, relieving symptoms such as palpitations, anxiety, heat intolerance, and tremors. This medication is crucial in restoring thyroid function to a more balanced state, promoting overall well-being. It is prescribed by healthcare professionals based on individual patient conditions, and dosage adjustments are made to optimize therapeutic outcomes in managing hyperthyroidism. Regular monitoring ensures the effectiveness of treatment and minimal side effects.

Orally: Patients take Carbimazole orally as tablets, swallowing them whole with water, preferably at consistent times daily for optimal effectiveness, after meals, is advisable, preferably at consistent times daily. Adhering actively to these instructions is crucial, as ensuring regularity in dosage, timing, and handling potential food interactions enhances the medication's efficacy and safety profile. Ensuring strict adherence to prescribed guidelines allows for the best possible management of the condition while minimizing the risk of complications.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Tablets:5mg, 10mg, 15mg, 20mg.

Carbimazole is available in the form of tablets.

Dose Adjustment in Adult Patients:

Start with an initial dose of 15–60 mg per day, divided into two or three doses, and titrate the dosage against thyroid function until euthyroidism is reached.

Maintenance: 5–15 mg daily (may be taken all at once); change dosage to keep the thyroid in a euthyroid state.

Blocking-replacement regimen: initially 20–60 mg per day, along with levothyroxine. Treatment period: six to eighteen months.

While taking Carbimazole, specific dietary guidelines should be followed to ensure optimal effectiveness and safety. Eliminate caffeine-containing drinks and foods, such as regular coffee, black tea, soda, and energy drinks, as they can exacerbate hyperthyroidism symptoms. Follow a low-iodine diet incorporating egg whites, non-iodized salt, black coffee, tea, vegetable oils, honey, unsalted nuts, and fruits. Consume selenium-rich foods like shrimp, beef, chicken, eggs, spinach, and oatmeal to normalize thyroid levels efficiently. Exclude iodine-rich items such as iodized salt, dairy, supplements, egg yolks, shellfish, and soy-based products to support effective hyperthyroidism management.

The dietary restriction should be individualized as per patient requirements.

• Hypersensitivity to Carbimazole or any container component or ingredient in the formulation.
• Galactosaemia
• An acute pancreatitis history following the use of carbimazole or thiamazole, its active metabolite
• Severe haematological disorder, particularly granulocytopenia.
• Severe hepatic impairment

It is advised to stop carbimazole during radio-iodine to assess potential interactions and preserve therapeutic efficacy.

Caution should be taken as the medication includes lactose; consider the relevance for patients with lactose intolerance.

Regularly monitor creatine kinase levels in patients reporting myalgia; elevated levels could indicate muscle-related side effects.

Monitor for signs of bone marrow depression, necessitating vigilant observation and appropriate action if detected.

Signs of hepatic damage, like malaise or jaundice, should be reported by patients to ensure timely assessment and appropriate management.

In the presence of clinical infection evidence, exercise caution and perform a white blood cell count for early detection and potential complication management.

Regularly assess thyroid function, adjusting the dosage to maintain optimal therapeutic outcomes.

Advise patients to promptly report unexplained fever, sore throat, bruising, or bleeding, enabling timely intervention and evaluation of potential adverse effects.

Exercise caution when using carbimazole in patients with retrosternal goitre, as it may worsen the condition and potentially lead to tracheal obstruction. Conducting regular monitoring and implementing appropriate management in such cases is crucial.

Discontinue carbimazole permanently if acute pancreatitis develops, as it indicates a severe and potentially life-threatening adverse reaction. Immediate attention and careful management are essential in such cases.

It is unsafe to consume alcohol.

Avoid breastfeeding with carbimazole, as it may be excreted in human milk in small amounts.

Due to clear evidence of risk to the developing fetus, it is not safe to use during pregnancy.

Avoid caffeine, iodine-rich foods; include selenium-rich diet.

The adverse reactions related to Carbimazole can be categorized as:

• Common Adverse Effects: Gastrointestinal disturbances (e.g., nausea, vomiting), skin rash, and joint pain.
• Less Common Adverse Effects: Agranulocytosis, hepatitis, and exfoliative dermatitis.
• Rare Adverse Effects: Neuropathies, CNS stimulation or depression, and nephrotic syndrome.

Reports on post-marketing

Severe liver injury, including hepatic failure requiring liver transplantation or death, has been reported (pediatric population).

The clinically relevant drug interactions of Carbimazole are briefly summarized here.

Drug-Drug Interaction: Carbimazole may have interactions with some medications, such as digoxin, blood thinners (warfarin), asthma medications (theophylline), steroids (prednisolone), antibiotics (erythromycin), and treatments for high blood pressure (metformin).

Drug-Disease Interaction: Before taking carbimazole, let the physician know if you have ever had acute pancreatitis (inflammation of the pancreas), intrathoracic goitre (swelling in the neck), a significant blood disorder, severe liver disease, or bone marrow depression.

The common side effects of Carbimazole include:

Nausea

Headache

Joint pain

Dizziness

Itching

Changes in taste

Hair thinning

Gastrointestinal disturbance

Skin rash

Paresthesia(feeling of tingling or prickling)

• Pregnancy

Pregnancy Category D (FDA): Use in situations where there is no safer medication available and life is in danger. Evidence that human fetal risk exists.

If administered during pregnancy, carbimazole and its active metabolite methimazole crosses the placenta. Although neonatal thyroid abnormalities are unlikely with standard maternal doses and monitored thyroid status, congenital malformations have been observed. Studies indicate a higher incidence of congenital malformations in untreated hyperthyroidism cases compared to carbimazole-treated ones. However, a causal link between carbimazole and methimazole exposure cannot be ruled out, particularly for choanal atresia and aplasia cutis congenita. Consequently, carbimazole usage in non-pregnant women of childbearing potential requires an individual risk/benefit assessment. In pregnancy, carbimazole is preferred when propylthiouracil is unsuitable, necessitating careful dose regulation and potential discontinuation before term to mitigate neonatal complications. The blocking-replacement regimen is discouraged during pregnancy due to limited thyroxine placental transfer. Pregnant women with hyperthyroidism should receive adequate treatment to prevent maternal and fetal complications. Notably, carbimazole usage during pregnancy demands rigorous individual risk evaluation, restricted to the lowest effective dose, with continuous maternal, fetal, and neonatal monitoring. Epidemiological studies and spontaneous reports suggest carbimazole may cause congenital malformations, warranting cautious administration during pregnancy. Reported malformations include aplasia cutis congenita, craniofacial abnormalities, exomphalos, oesophageal atresia, omphalomesenteric duct anomaly, and ventricular septal defect. Strict individual benefit/risk assessment is imperative, emphasizing careful dose management and vigilant monitoring during pregnancy.

• Nursing Mothers

Breastfeeding should not continue if therapy is continued during lactation since carbimazole is released in breast milk.

• Pediatric Use

As per FDA, the safety and efficacy of Carbimazole in Pediatric patients have not been established.

However, when using this population, utmost caution should be taken.

Dose Adjustment in Pediatric Patients:

Use in adolescents (3 to 17 years old): The first dose is typically 15 mg daily, with adjustments based on response.

Use in young children (those under two years old): There has yet to be a thorough analysis of carbimazole's safety and effectiveness in kids younger than two. Therefore, it is not advised to use carbimazole in children under the age of two.

• Geriatrics (> 65 years old)

As per the FDA, the safety and efficacy of Carbimazole in elderly patients above 65 have not been extensively studied or established.

Insufficient data from Carbimazole studies involve subjects aged 65 or older. Clinical experience hasn't shown differences between elderly and younger patients. Caution in dose selection for elderly patients is essential, considering potential hepatic, renal, or cardiac function declines and other concurrent medical conditions or medications.

Dose Adjustment in Kidney Impairment Patients:

Carbimazole should be given with caution, especially with a history of Kidney diseases/conditions. The dose may be adjusted as required.

Dose Adjustment in Hepatic Impairment Patients:

Mild to moderate Impairment: Carbimazole should be used with caution in patients with liver disease. Dose adjustment may be needed

Severe Impairment: Not recommended

The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of Carbimazole.

Signs and Symptoms

Overconsumption of Carbimazole could lead to nausea, vomiting, headache, joint pain, fever, pruritus, and oedema. Severe cases may exhibit aplastic anemia, agranulocytosis, hepatitis, neuropathies, and CNS stimulation or depression.

Management

There is no specific antidote or treatment for overdosage of Carbimazole, so treatment typically involves symptomatic and supportive measures. Gastric lavage or induced vomiting could be considered if the ingestion occurred within an hour, followed by the administration of activated charcoal to reduce further absorption of the drug from the gastrointestinal tract.

In severe cases, hospitalization may be necessary. Specific interventions include addressing nausea, vomiting, and associated symptoms. Glucocorticoids may be considered for agranulocytosis. Regular blood cell count assessments are crucial. Beta-blockers can manage signs like tachycardia and tremors. Granulocyte colony-stimulating factor (G-CSF) may be used in cases of bone marrow suppression. Plasmapheresis or hemodialysis could be explored in extreme situations to eliminate excess carbimazole.

Timely medical intervention plays a crucial role in managing Carbimazole overdose, ensuring careful monitoring and proper care to address symptoms and prevent complications.

Pharmacodynamics

The pharmacodynamic effects of carbimazole are achieved by the inhibition of thyroperoxidase, an enzyme that is essential for the manufacture of thyroid hormones. Carbamazole efficiently inhibits the synthesis of thyroid hormones by preventing iodine from being incorporated into tyrosine residues. This method of action contributes to the overall management of thyroid problems by easing the symptoms of hyperthyroidism and restoring thyroid function to a more balanced state.

Pharmacokinetics:

Absorption: Carbimazole undergoes rapid and extensive absorption in the intestines, with 90-100% absorption within 15-30 minutes. It swiftly transforms into its active metabolite, methimazole, detectable in the blood. The peak plasma concentration of methimazole occurs about one hour after a single carbimazole dose, reaching 0.2 to 1.0 μg/l within 1-2 hours following a 60 mg dose.

Distribution: The blood half-life varies from 4-12 hours, more associated with individual variability than thyroid status. Methimazole, with a distribution volume of approximately 40 litres and binding up to 40% to plasma proteins, concentrates rapidly in the thyroid gland, extending carbimazole's activity.

Metabolism: Carbimazole undergoes hydrolysis and enzymatic decarboxylation in the blood, transforming into methimazole. It further undergoes oxidative decomposition in the liver and thyroid, producing a half-life of 5.3 to 5.4 hours. Methimazole's apparent plasma half-life is 6.4 hours, prolonged in the thyroid (about 20 hours), correlating with the duration of a single dose's effect.

Excretion: Elimination involves over 90% of orally administered carbimazole excreted in urine as methimazole or its metabolites, with 10% enterohepatic circulation. About 7% of methimazole is excreted unchanged. Methimazole crosses the placenta and appears in breast milk, with a plasma-milk ratio approaching unity.

• Grebe SK, Feek CM, Ford HC, Fagerström JN, Cordwell DP, Delahunt JW, Toomath RJ. A randomized trial of short-term treatment of Graves' disease with high-dose carbimazole plus thyroxine versus low-dose carbimazole. Clin Endocrinol (Oxf). 1998 May;48(5):585-92. doi: 10.1046/j.1365-2265.1998.00446.x. PMID: 9666870.

• Page SR, Sheard CE, Herbert M, Hopton M, Jeffcoate WJ. A comparison of 20 or 40 mg per day of carbimazole in the initial treatment of hyperthyroidism. Clin Endocrinol (Oxf). 1996 Nov;45(5):511-6. doi: 10.1046/j.1365-2265.1996.00800.x. Erratum in: Clin Endocrinol (Oxf) 1997 Feb;46(2):240. PMID: 8977745.

• Shivaprasad C, Prasanna Kumar KM. Long-term carbimazole pretreatment reduces the efficacy of radioiodine therapy. Indian J Endocrinol Metab. 2015 Jan-Feb;19(1):84-8. doi: 10.4103/2230-8210.146865. PMID: 25593832; PMCID: PMC4287787.

• Khan Z, Afifi W, Muhammad SA, Warrier V. Carbimazole-Induced Agranulocytosis in a Previously Stable Patient: A Case Report and Literature Review. Cureus. 2022 Apr 13;14(4):e24115. doi: 10.7759/cureus.24115. Erratum in: Cureus. 2023 Jan 17;15(1):c96. PMID: 35573582; PMCID: PMC9106535.

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