Telmisartan + Hydrochlorothiazide

Telmisartan + Hydrochlorothiazide is an antihypertensive agent belonging to the Angiotensin II Receptor Blocker class and Thiazide Diuretics.

Telmisartan + Hydrochlorothiazide is approved for treating adults' hypertension (high blood pressure). It combines Telmisartan (Angiotensin II receptor blocker) and Hydrochlorothiazide (a diuretic) to reduce blood pressure and more effectively treat hypertension.

Telmisartan is effectively absorbed from the gastrointestinal system more gradually, reaching its peak levels after 0.5 to 1 hour. Similarly, Hydrochlorothiazide is readily absorbed. Within two to four hours of oral dosing, both medications reach peak plasma concentrations. Hydrochlorothiazide is excreted mainly through the kidneys, whereas Telmisartan is primarily eliminated in the faeces.

The common side effect of Telmisartan + Hydrochlorothiazide is dizziness. Shortness of breath, nausea, diarrhoea, flu-like symptoms, fatigue, and changes in heartbeat are a few additional side effects.

Telmisartan + Hydrochlorothiazide is available as a tablet for convenient administration.

Telmisartan + Hydrochlorothiazide is available in the United States, Canada, the United Kingdom, India and Australia.

Telmisartan + Hydrochlorothiazide is an antihypertensive agent belonging to the Angiotensin II Receptor Blocker class and Thiazide Diuretics.

Telmisartan: Telmisartan selectively prevents angiotensin II from binding to the AT1 receptor in a variety of tissues, the vascular smooth muscles and the adrenal gland, hence preventing angiotensin II's vasoconstrictor and aldosterone-secreting effects. Limiting the effects of angiotensin II lowers systemic vascular resistance since it is a vasoconstrictor that induces aldosterone production and release.

The time taken for Telmisartan to show its effect must be clinically established.

Telmisartan may remain in your body for approximately 1-2 days.

Clearance: 800 mL/min

The Tmax was found within 0.5-1 hours following the administration of Telmisartan, and the Cmax was about 522.29 ng/mL.

Hydrochlorothiazide: Thiazide diuretic lowers blood pressure and reduces oedema by inhibiting Na reabsorption in distal renal tubules, increasing Na and water excretion.

The Onset of action of Hydrochlorothiazide occurs within 2 hours of its administration.

The Duration of Action for Hydrochlorothiazide in the body is approximately 6-12 hours.

The Tmax was found within 1-5 hours, and Cmax 70 to 490 ng/mL following the administration of Hydrochlorothiazide.

Protein Bound: 68%

Clearance: 335 mL/min

Vd: 3.6-7.8 L/kg

Half-Life: 6-15 hr

Synergistic Benefits: Telmisartan + Hydrochlorothiazide provides a synergistic approach to managing hypertension. Angiotensin II receptor blocker (ARB) Telmisartan relaxes blood arteries. Diuretics like Hydrochlorothiazide help the body flush out extra water and salt. They exert more overall control by lowering blood pressure through various mechanisms. An efficient and comprehensive strategy for managing hypertension is provided by this combination, which reduces the risk of cardiovascular events, including strokes and heart attacks, while also minimizing fluid retention.

When one medication fails to regulate your blood pressure, these medications are combined. Thus, they work synergistically to help lower blood pressure and manage hypertension effectively.

Data Onset of action of Telmisartan + Hydrochlorothiazide effects is shown within a few hours post-administration

Data duration of action of Telmisartan + Hydrochlorothiazide effects can last up to 24 hours—following oral administration.

The Data of Tmax of Telmisartan + Hydrochlorothiazide typically ranges from 0.5 to 4 hours after oral administration.

The Cmax (peak plasma concentration) of Telmisartan is approximately 0.5 to 4.5 ng/mL, while that of Hydrochlorothiazide is about 70 to 490 ng/mL, depending on the dose and individual variability.

Telmisartan + Hydrochlorothiazide is available in tablets.

Tablets: To be swallowed whole with water/liquid.

As the physician recommends, take the medication orally once daily, generally with or without a meal.

Telmisartan is approved to treat hypertension and heart failure and prevent the death that follows a heart attack. Telmisartan can be used on its own or in combination with other drugs.

• Hydrochlorothiazide may also be used to treat patients with diabetes insipidus and prevent kidney stones in patients with high calcium levels in their blood.
• Thiazide diuretic Hydrochlorothiazide treats oedema and hypertension in congestive heart failure, liver cirrhosis, and corticosteroid and oestrogen treatment.
• Telmisartan + Hydrochlorothiazide combination is used to treat hypertension or high blood pressure. Strokes, heart attacks, and renal issues can all be prevented by lowering excessive blood pressure.
• This combination may also reduce the risk of cardiovascular events such as strokes and heart attacks in patients with hypertension and other risk factors.

Telmisartan + Hydrochlorothiazide is an antihypertensive agent belonging to the Angiotensin II Receptor Blocker class and Thiazide Diuretics.

Telmisartan: Telmisartan helps to reduce high blood pressure or hypertension by relaxing blood vessels to improve blood flow.

Hydrochlorothiazide: People with congestive heart failure, liver cirrhosis, renal problems, or oedema brought on by using steroids or oestrogen and hypertension are treated with Hydrochlorothiazide.

The Telmisartan + Hydrochlorothiazide combination benefits hypertension by effectively lowering blood pressure and related conditions through distinct mechanisms of action. Telmisartan blocks the action of angiotensin II, relaxing blood vessels. Hydrochlorothiazide is a diuretic that reduces fluid retention. Together, they provide comprehensive blood pressure control, reduce the risk of cardiovascular events, and offer convenience with a single-pill regimen, promoting medication adherence and patient well-being.

Telmisartan + Hydrochlorothiazide is approved for use in the following clinical indications:

• Patients who have already been titrated on the individual components, Hydrochlorothiazide and Telmisartan, are indicated for therapy of hypertension.

• This combination therapy might help to lower the risk of cardiovascular events, including heart attacks and strokes, in patients with hypertension and other cardiovascular risk factors.

• It is indicated to be used in individuals who would benefit from combination therapy or as the first line of treatment for patients likely to require many medications to achieve their blood pressure goals.

• To prevent accumulation of excess fluid in the body's tissues. People who endure fluid retention due to several ailments will benefit from this effect.

Orally: Telmisartan + Hydrochlorothiazide is available as a tablet that can be taken orally. Telmisartan + Hydrochlorothiazide should be taken on an empty stomach or with food. The tablets should be swallowed whole with a glass of water, and avoid crushing or chewing them. It is advised to take it regularly at a fixed time each day for optimal effectiveness. The precise composition and the patient's medical condition influence the dosage and frequency. To maintain proper blood pressure control, it's crucial to carefully follow the doctor's instructions and avoid abrupt discontinuation of medication without consultation. Always follow the healthcare provider's instructions for dosage and administration.

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

Telmisartan + Hydrochlorothiazide has various strengths, such as 40mg+12.5mg, 80mg+12.5mg or 80mg+25mg

Dosage Adjustment for Adult Patients

Hypertension

One tablet, used orally daily, contains 80–160 mg of Telmisartan and 12.5–25 mg of Hydrochlorothiazide.

Telmisartan + Hydrochlorothiazide is available in the form of Oral tablets.

Telmisartan + Hydrochlorothiazide should be used in treating hypertension, along with appropriate dietary restrictions.

Avoid consumption of a high-salt or high-sodium diet while taking Hydrochlorothiazide.

High caffeine intake may affect blood pressure. Consider moderating caffeine consumption.

Avoid excessive consumption of alcohol, grapefruit or grapefruit juice while taking Telmisartan, as it may interact with the medication.

When taking Telmisartan, avoid foods high in potassium, such as bananas, nuts, and sweet potatoes, as they may result in Hyperkalemia or high blood potassium levels.

While taking this combination, it is advised to stay hydrated, maintain a rich, balanced diet low in saturated fats and cholesterol, and consume plenty of vegetables, whole grains, fruits, and lean proteins.

The dietary restriction should be individualized as per patient requirements.

Telmisartan + Hydrochlorothiazide may be contraindicated in patients with the following conditions:-

• Hypersensitivity such as anaphylaxis, angioedema (drug components such as Telmisartan, Hydrochlorothiazide or sulfonamide-derived substance)

• Anuria

• Pregnancy: Significant risk of fetal/neonatal morbidity and death during the second and third trimesters of pregnancy

• Co-administer aliskiren in patients with diabetes mellitus; avoid the use of aliskiren with benazepril in patients with renal impairment (GFR <60 ml/min/1.73 m²)

• Severe Renal impairment (<30 mL/min)

• Severe hepatic impairment

• History of Angioedema

• Hypotension

The treating physician must closely monitor the patient and keep pharmacovigilance as follows.

• Syncope or symptomatic hypotension may happen in patients with activated renin-angiotensin system, such as volume- or salt-depleted patients; correct volume or salt depletion before administration of therapy

• Patients who have significant renal or hepatic impairment should be titrated cautiously.

• Acute short-term myopia and angle-closure glaucoma can emerge from the sulfonamide hydrochlorothiazide's capacity to trigger an atypical response. It is essential to stop taking Hydrochlorothiazide as soon as possible to manage acute angle-closure glaucoma, which, if left untreated, can result in irreversible visual loss.

• Photosensitivity could happen; advise patients to use sunblock and get frequent skin cancer screenings

• Use thiazides cautiously if individuals have mild to moderate liver damage or progressing liver disease.

• Maintain fluid and electrolyte imbalance

• When treating individuals with hypercalcemia, Hydrochlorothiazide may cause blood calcium levels to rise and reduce urine calcium excretion.

• Compared to monotherapy, dual blockade of the renin-angiotensin system with ARBs, ACE inhibitors, or aliskiren increases the risk of hypotension, Hyperkalemia, and impaired renal function (including acute renal failure).

• Hydrochlorothiazide may impair glucose tolerance, elevate blood uric acid levels, raise cholesterol and triglyceride levels, and aggravate hyperuricemia and gout in hypersensitive individuals.

• Hydrochlorothiazide can result in hypomagnesemia and hyponatremia; thiazides have been proven to increase urine excretion of magnesium; hypomagnesemia can result in hypokalemia, which may be difficult to cure despite potassium replacement; periodically check the serum electrolytes

• Precautions should be taken if one has anuria, bilateral renal artery stenosis, aortic mitral stenosis, hepatic impairment, hypercholesterolemia, hypercalcemia, parathyroid illness, systemic lupus erythematosus, hypertension, or hypercalcemia.

• When giving patients Hydrochlorothiazide, be extra cautious if they have a history of allergies or bronchial asthma since these patients are more likely to experience hypersensitivity responses, which can happen to any individual. However, they are more probable in these patients.

It is unsafe to consume alcohol with Telmisartan + Hydrochlorothiazide

Telmisartan + Hydrochlorothiazide is not recommended during breastfeeding due to the risk of severe adverse effects.

Unsafe to use during pregnancy.

Avoid or minimize the consumption of grapefruit or grapefruit juice. Caution should be taken while consuming caffeine, potassium or sodium-rich foods, and alcohol, as it may interact with the medication.

The adverse reactions related to Telmisartan + Hydrochlorothiazide can be categorized as

• Common: Dizziness, hypotension, nausea, fatigue and Elevated blood urea nitrogen levels
• Less Common: Muscle cramps, blurred vision, blood glucose and potassium levels alterations, abnormal liver function tests.
• Rare: Allergic reactions, gout and kidney dysfunction.

Reports on Post-marketing

Syncope

Disorders of metabolism and nutrition: hyponatremia and hypoglycemia in diabetic patients

Hydrochlorothiazide: melanoma-free skin cancer

The clinically relevant drug interactions of Telmisartan + Hydrochlorothiazide are briefly summarized here.

• Lithium: Lithium toxicity and blood lithium concentration increase when angiotensin II receptor antagonists, such as Telmisartan, are used concurrently with lithium. When using lithium concurrently, maintain a close watch on the blood levels.
• Antidiabetic drugs (oral agents and insulin) dosage adjustment of the antidiabetic drug may be required.
• Digoxin: Digoxin's peak plasma concentration increased by 49% and its trough concentration by 20% when Telmisartan was delivered. Digoxin levels should be monitored during initiating, modifying, and stopping Telmisartan to ensure that the digoxin level remains within the therapeutic range.
• Corticosteroid, ACTH: Increased electrolyte loss, especially hypokalemia.
• Pressor amines (e.g., norepinephrine): Potentially reduced response to pressor amines, but not by enough to permit use.
• Cholestyramine and colestipol resins: Cholestyramine and colestipol resins bind Hydrochlorothiazide and reduce it by up to 85% and 43%, respectively, in the gastrointestinal system.
• Non-steroidal anti-inflammatory drugs: Non-steroidal anti-inflammatory drugs (NSAIDs) can decrease the intended benefits of diuretics like Hydrochlorothiazide when used concurrently. A thorough observation is recommended to determine how effective a diuretic is in this combination. Combining NSAIDs with angiotensin II receptor antagonists, such as Telmisartan, may cause renal problems in older individuals, those with low fluid volume, or patients with impaired kidney function. These problems, however, may be treatable. When taking Telmisartan plus NSAIDs, such as selective COX-2 inhibitors, it is advisable to have regular renal function tests since NSAIDs might decrease Telmisartan's antihypertensive impact.

• Tiredness

• Dizziness

• Nausea

• Diarrhoea

• A sinus infection.

• Flu-like symptoms

• Infection of the upper respiratory tract

Telmisartan + Hydrochlorothiazide should be prudent in the following group of special populations.

• Pregnancy:

Fetal/ Neonatal adverse reactions

Telmisartan: Pregnancy Categories C (first trimester) and D (second and third trimesters)

When used during the second or third trimester of pregnancy, Telmisartan, like other drugs that affect the renin-angiotensin system, can result in morbidity and death for the foetus and the newborn. When given to a pregnant woman, Telmisartan has the potential to harm the foetus, causing impairment of foetal renal function and production of oligohydramnios that can lead to skeletal malformations.

Hydrochlorothiazide: Pregnancy Category B

Studies in which pregnant mice and rats received dosages of up to 3000 and 1000 mg hydrochlorothiazide/kg, respectively, orally during their respective periods of major organogenesis did not show any signs of harm to the foetus.

Thiazides can penetrate the placenta and result in placental hypoperfusion. They accumulate in the amniotic fluid and can cause thrombocytopenia or foetal or neonatal jaundice. Avoid use

Due to the high potential risk to the foetus, avoid the Telmisartan + Hydrochlorothiazide combination when pregnant. If pregnancy is detected, stop immediately according to pregnancy recommendations. High blood pressure during pregnancy raises the chances of complications for both the mother and the baby, including conditions like pre-eclampsia and premature birth. Close monitoring and proper management are essential.

Certain medications affecting the renin-angiotensin system, used by pregnant women in the later stages of pregnancy, can lead to low amniotic fluid levels. This may cause issues like reduced fetal kidney function, lung problems, skeletal deformities, low blood pressure, and even death.

When using this drug while expecting or planning a pregnancy, use caution and consult a physician.

• Lactating Mothers

Minimal is known about the prevalence of these medicines in human milk and how they affect newborns. Hydrochlorothiazide and Telmisartan can be detected in animal and human milk, respectively. It is not advised to breastfeed while taking this medication combination since there might be severe side effects in breastfed infants.

Data

From 4 to 8 hours after injection, Telmisartan was identified in the milk from lactating rats at concentrations 1.5 to 2 times those seen in plasma.

• Pediatric Use

As per FDA, safety and effectiveness in the pediatric population have not been established.

Neonates with a history of in-utero drug exposure should be cautiously monitored for hypotension, oliguria, and Hyperkalemia.

• Geriatric Use

Geriatric people should have their use of Telmisartan + Hydrochlorothiazide closely monitored. Elderly people may be more vulnerable to adverse drug reactions and drug interactions. It is essential to closely monitor liver and kidney function and any possible medication interactions. Depending on the individual's medical situation and drug regimen, dosage modifications may be required. It's crucial to monitor patients and consult with medical professionals regularly.

Dosage Adjustment in Kidney Impairment Patient

Renal impairment

Mild (CrCl 60 to 90 mL/min) to moderate (CrCl 30 to 60 mL/min): Specific dosage adjustments may not be necessary.

Severe (CrCl ≤30 mL/min): Administer slowly or not recommended.

Hemodialysis patients are more likely to have hypotension

Dosage Adjustment in Hepatic Impairment Patient

Hepatic impairment

Initiate with a lower dose of 2.5 mg amlodipine and increase the amount gradually. It is expected that biliary blockage or hepatic insufficiency may limit clearance.

The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of Telmisartan + Hydrochlorothiazide. Overconsumption of this combination could lead to symptoms such as a fast heartbeat, severe dizziness and fainting.

There is no specific antidote or treatment for excessive intake of Telmisartan + Hydrochlorothiazide. However, immediate medical attention is essential.

Telmisartan + Hydrochlorothiazide should be terminated immediately when an overdose is suspected or if any unusual symptoms occur after intake. Management typically involves supportive measures and symptomatic treatment. Supportive therapy should be given, addressing any symptoms that persist or worsen. Activated charcoal may also be considered if the overdose is detected shortly after ingestion to reduce absorption. Monitoring the patient's vital signs and correcting any electrolyte imbalances, especially Hyperkalemia (high potassium levels), is crucial. Physical treatment might be added if necessary.

Pharmacodynamic of Telmisartan + Hydrochlorothiazide

Telmisartan: Telmisartan is a nonpeptide, orally active angiotensin II antagonist that targets the AT1 receptor subtype alone. The angiotensin II receptor blockers (ARBs) currently on the market have the lowest affinity for the AT2 receptor and the highest affinity for the AT1 receptor. Telmisartan also has the potential to be an agonist for PPAR. This nuclear receptor controls the transcription of genes related to lipid and glucose metabolism and anti-inflammatory responses. Clinical studies are being conducted now to examine this possibility. ACE (angiotensin-converting enzyme) converts angiotensin I to angiotensin II, which is a crucial part of the renin-angiotensin system and is mainly responsible for vasoconstriction, aldosterone release, cardiac stimulation, and renal sodium chloride reabsorption. Telmisartan works by preventing the aldosterone-releasing and vasoconstrictive effects of angiotensin II.

Hydrochlorothiazide: Thiazides have been shown to have acute antihypertensive effects secondary to a natriuretic impact on blood volume and cardiac output; however, a direct vasodilatory mechanism has also been hypothesized. Plasma volume returns to normal after prolonged dosing, although peripheral vascular resistance is reduced. Hydrochlorothiazide has an antihypertensive impact. However, the specific mechanism is unknown. Normal blood pressure is unaffected by thiazides. Within two hours of the dose, the effects start to manifest, reaching their peak at around four hours and lasting up to 24 hours.

Pharmacokinetics of Telmisartan + Hydrochlorothiazide

Absorption

Telmisartan: Peak Telmisartan concentrations are reached at approximately 0.5–1 hours of oral ingestion. Consuming food decreases bioavailability, which causes a 6% drop in the plasma concentration-time curve for the 40 mg pill. The absolute bioavailability of Telmisartan changes with 42% and 58% for 40 mg and 160 mg dosages, respectively. Its pharmacokinetics display nonlinearity in the 20–160 mg dosage range, with larger doses producing more than proportionate increases in plasma concentrations (Cmax and AUC). The half-life of Telmisartan is about 24 hours. With a repeated dosing accumulation index in plasma, a once-daily dose results in plasma concentrations at around 10–25% of peak values.

Hydrochlorothiazide: Hydrochlorothiazide is well absorbed (65% to 75%) after oral administration. Absorption of Hydrochlorothiazide is lower in patients with congestive heart failure.

Distribution

Telmisartan: High albumin levels and 1-acid glycoprotein binding levels are seen in plasma proteins. The estimated 500-litre volume of Telmisartan's dispersion suggests extra tissue binding.

Hydrochlorothiazide: The given dosage has a linear relationship with plasma concentrations. Whole blood has hydrochlorothiazide concentrations of 1.6–1.8 times greater than plasma. Serum protein binding has been estimated to range from 40% to 68%. According to reports, the plasma elimination half-life is between 6 and 15 hours.

Metabolism

Telmisartan: Telmisartan is metabolized via conjugation to produce an acyl glucuronide, the parent compound's glucuronide and the only metabolite detected in human plasma and urine. The metabolism of Telmisartan does not include the isoenzyme cytochrome P450. No matter the dose, Telmisartan's total plasma clearance is more significant than 800 mL/min.

Hydrochlorothiazide: Hydrochlorothiazide is eliminated primarily by renal pathways.

Excretion

Telmisartan: When 14C-labeled Telmisartan is delivered intravenously or orally, the bulk of the dosage is excreted in the faeces intact via biliary excretion, and only trace quantities were detected in the urine.

Hydrochlorothiazide: More than 95% of the absorbed dosage is excreted in urine as an unaltered substance at oral doses of 12.5 to 100 mg, with 55% to 77% of the given amount appearing in the urine.

Therapeutic benefits of a combination of Telmisartan + Hydrochlorothiazide

• Telmisartan + Hydrochlorothiazide is primarily prescribed to treat hypertension (high blood pressure) as it provides a potent antihypertensive effect. Telmisartan is an angiotensin II receptor blocker (ARB) which relaxes blood vessels. Hydrochlorothiazide is a diuretic that helps the body remove excess sodium and water, reducing fluid volume and blood pressure. This combination provides a dual-action approach to controlling hypertension.
• The Telmisartan + Hydrochlorothiazide combination helps to minimize the risk of cardiovascular events, including heart attacks and strokes, by significantly decreasing blood pressure. Maintaining healthy blood pressure levels is essential to protect the heart, blood vessels, and other organs.
• As a diuretic, Hydrochlorothiazide helps in controlling the body's fluid balance. People susceptible to oedema or fluid retention, which is frequently linked to heart failure, liver illness, or renal problems, may find this helpful. It reduces swelling and pain by facilitating the removal of extra fluid.

• Parati, G., Bilo, G., Redon, J. et al. The effects of Telmisartan alone or with Hydrochlorothiazide on morning and 24-h ambulatory BP control: results from a practice-based study (SURGE 2). Hypertens Res 36, 322–327 (2013). https://doi.org/10.1038/hr.2012.171
• Harold Bays, Pingjin Gao, Birgit Völker, Michaela Mattheus, Luis M. Ruilope, Dingliang Zhu, "Efficacy of Single-Pill Combination of Telmisartan 80 mg and Hydrochlorothiazide 25 mg in Patients with Cardiovascular Disease Risk Factors: A Prospective Subgroup Analysis of a Randomized, Double-Blind, and Controlled Trial", International Journal of Hypertension, vol. 2013, Article ID 749830, 13 pages, 2013. https://doi.org/10.1155/2013/749830
• Roberto Fogari, Paola Preti, Annalisa Zoppi, Luca Corradi, Carlo Pasotti, Andrea Rinaldi, Amedeo Mugellini, Effect of Telmisartan/Hydrochlorothiazide Combination Versus Nifedipine GITS on Ambulatory Blood Pressure and Sympathetic Activation, American Journal of Hypertension, Volume 18, Issue 5, May 2005, Pages 577–583, https://doi.org/10.1016/j.amjhyper.2004.11.020
• Neldam, Steen & Schumacher, Helmut & Kjeldsen, Sverre & Neutel, Joel. (2014). Telmisartan in combination with hydrochlorothiazide 12.5 mg for the management of patients with hypertension. Current medical research and opinion. 30. 1-0. 10.1185/03007995.2014.924912.

Carcinogenesis, Mutagenesis, Impairment of Fertility

• Telmisartan and Hydrochlorothiazide

The combination of Telmisartan and Hydrochlorothiazide has not been studied for carcinogenicity, mutagenicity, or fertility.

• Telmisartan

In experiments where mice and rats were given Telmisartan in their food for up to 2 years, no indication of a cancer risk was found. When adjusted the body surface area, the highest doses administered to mice (1000 mg/kg/day) and rats (100 mg/kg/day) were about 59 and 13 times greater than the maximum recommended human dosage (MRHD) of Telmisartan (80 mg/day), respectively.

Telmisartan-related effects at the gene or chromosomal level were not detected in tests for genetic harm. These tests involved working with bacteria (Salmonella and E. coli), hamster cell gene alterations, testing the chromosomes of human lymphocytes, and a mouse test for micronuclei.

At a maximum dose of 100 mg/kg/day, around 13 times the MRHD when adjusted for body surface area, neither male nor female rats' reproductive abilities were negatively impacted. Telmisartan exposure was at least 50 times more in rats receiving this dosage than in people receiving the MRHD (80 mg/day).

• Hydrochlorothiazide

The National Toxicology Programme (NTP) conducted extensive two-year experiments in mice and rats. However, neither species showed any evidence that Hydrochlorothiazide had any potential to cause cancer when administered to female mice at doses up to about 600 mg/kg/day or to male and female rats at doses up to about 100 mg/kg/day. However, NTP found conflicting data about the hepatocarcinogenicity of male mice.

In tests using the Chinese hamster ovary (CHO) test for chromosomal aberrations, mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene, Hydrochlorothiazide was found to be non-genotoxic in vitro. Positive test outcomes were achieved in the in vitro CHO Sister Chromatid Exchange (clastogenicity) assay, the Mouse Lymphoma Cell (mutagenicity) assay, and the Aspergillus nidulans non-disjunction assay.

In addition, mice and rats treated to dosages of up to 100 mg per kg and 4 mg per kg of Hydrochlorothiazide through their diets before mating and throughout pregnancy did not adversely affect their ability to reproduce.

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