Telmisartan/Hydrochlorothiazide

Description

Telmisartan, USP is chemically described as 4’-[4-methyl-6-(1-methyl-2-benzimidazolyl)-2-propyl-1-benzimidazolyl methyl]-2-biphenylcarboxylic acid. Its empirical formula is C33H30N4O2, and it has a molecular weight of 514.62. Telmisartan, USP appears as a white or slightly yellowish crystalline powder. It is practically insoluble in water, slightly soluble in methanol, sparingly soluble in methylene chloride, and dissolves in 1M sodium hydroxide.

Hydrochlorothiazide, USP is chemically described as 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its empirical formula is C7H8ClN3O4S2, with a molecular weight of 297.74. Hydrochlorothiazide, USP is a white or practically white, practically odorless, crystalline powder. It is very slightly soluble in water, freely soluble in sodium hydroxide solution, n-butylamine, and dimethylformamide, sparingly soluble in methanol, and insoluble in ether, chloroform, and dilute mineral acids.

Telmisartan and Hydrochlorothiazide Tablets, USP are formulated for oral administration in three combinations: 40 mg/12.5 mg, 80 mg/12.5 mg, and 80 mg/25 mg. The tablets contain inactive ingredients including colloidal silicon dioxide, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, mannitol, meglumine, povidone K-25, sodium hydroxide, sodium stearyl fumarate, and talc. The 40 mg/12.5 mg, 80 mg/12.5 mg, and 80 mg/25 mg tablets contain ferric oxide red, while the 80 mg/25 mg tablets also contain ferric oxide yellow. Telmisartan and Hydrochlorothiazide Tablets, USP are hygroscopic and require protection from moisture.

Uses and Indications

Telmisartan and hydrochlorothiazide tablets are indicated for the treatment of hypertension, either as monotherapy or in combination with other antihypertensive agents, to effectively lower blood pressure. The reduction of blood pressure is associated with a decreased risk of both fatal and nonfatal cardiovascular events, including strokes and myocardial infarctions.

It is important to note that telmisartan and hydrochlorothiazide tablets are not indicated for initial therapy in the management of hypertension.

Dosage and Administration

The usual starting dose for the medication is 80 mg/12.5 mg administered once daily. Based on the patient's response and clinical judgment, the dose may be titrated up to a maximum of 160 mg/25 mg as needed.

For patients with biliary obstructive disorders or hepatic insufficiency, it is recommended to initiate treatment at a lower dose of 40 mg/12.5 mg once daily. Careful monitoring of these patients is advised to assess tolerance and efficacy, with adjustments made as clinically appropriate.

Contraindications

Use of this product is contraindicated in patients with hypersensitivity to telmisartan or any of its components. Additionally, it is contraindicated in individuals with anuria, as this condition may impair renal function. Co-administration with aliskiren is contraindicated in patients with diabetes due to the increased risk of adverse effects.

Warnings and Precautions

Fetal toxicity is a significant concern associated with the use of telmisartan and hydrochlorothiazide. It is imperative that these medications be discontinued as soon as pregnancy is detected, as drugs that act directly on the renin-angiotensin system can lead to serious injury or death of the developing fetus. Healthcare professionals must ensure that patients are aware of this risk and take appropriate measures to avoid fetal or neonatal exposure.

Prior to initiating therapy, it is essential to correct any volume or salt depletion. Clinicians should closely monitor patients for signs and symptoms of hypotension, particularly in those who may be susceptible. Regular assessment of renal function and potassium levels is recommended for these patients to prevent potential complications. Additionally, healthcare providers should remain vigilant for clinical signs of fluid or electrolyte imbalance, which may arise during treatment.

Patients may also experience hypersensitivity reactions, and it is crucial to monitor for any such adverse effects. Furthermore, there is a risk of acute myopia and secondary angle-closure glaucoma associated with the use of these medications, necessitating careful observation of patients for any visual disturbances.

To ensure safe use, regular laboratory tests to monitor renal function and potassium levels should be conducted in susceptible patients. This proactive approach will help mitigate risks and enhance patient safety during treatment.

Side Effects

Patients receiving telmisartan and hydrochlorothiazide may experience a range of adverse reactions. Common adverse reactions, occurring in 2% or more of patients, include upper respiratory tract infection, dizziness, sinusitis, diarrhea, fatigue, influenza-like symptoms, and nausea.

Serious warnings associated with this medication include the potential for fetal toxicity. It is imperative that telmisartan and hydrochlorothiazide be discontinued as soon as pregnancy is detected, as drugs that act directly on the renin-angiotensin system can cause injury or death to the developing fetus. To mitigate risks, healthcare providers should correct any volume or salt depletion prior to initiating therapy and monitor for signs of hypotension. Additionally, renal function and potassium levels should be closely observed in susceptible patients, and clinical signs of fluid or electrolyte imbalance should be monitored.

Other notable adverse reactions include hypersensitivity to telmisartan or any of its components, anuria, and the potential for adverse effects when co-administered with aliskiren in patients with diabetes.

In cases of overdosage, the manifestations associated with telmisartan may include hypotension, dizziness, and tachycardia, with bradycardia potentially occurring due to parasympathetic (vagal) stimulation. For hydrochlorothiazide, the most common signs and symptoms observed in patients with an overdose are those resulting from electrolyte depletion, such as hypokalemia, hypochloremia, and hyponatremia, as well as dehydration due to excessive diuresis.

Drug Interactions

There are currently no documented drug interactions associated with the use of this medication. Additionally, there is no information available regarding interactions with laboratory tests. As such, no specific recommendations for dosage adjustments or monitoring are warranted at this time.

Packaging & NDC

The table below lists all NDC Code configurations of Telmisartan and Hydrochlorothiazide, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

Safety and effectiveness of telmisartan and hydrochlorothiazide tablets in pediatric patients have not been established.

In neonates with a history of in utero exposure to telmisartan and hydrochlorothiazide tablets, if oliguria or hypotension occurs, it is essential to support blood pressure and renal perfusion. Exchange transfusions or dialysis may be required to reverse hypotension and/or substitute for disordered renal function.

Geriatric Use

In controlled clinical trials, approximately 20% of patients treated with telmisartan/hydrochlorothiazide were aged 65 years or older, with 5% being 75 years of age or older. The data indicate that there are no overall differences in the effectiveness and safety of telmisartan/hydrochlorothiazide when comparing elderly patients to younger patients. However, it is important to note that while other clinical experiences have not identified significant differences in responses between these age groups, the possibility of greater sensitivity in some older individuals cannot be excluded.

When considering dose selection for geriatric patients, caution is advised. It is generally recommended to initiate treatment at the lower end of the dosing range. This recommendation is based on the increased likelihood of diminished hepatic, renal, or cardiac function in elderly patients, as well as the potential presence of concomitant diseases or other drug therapies that may affect treatment outcomes. Regular monitoring and assessment of these factors are essential to ensure the safe and effective use of telmisartan/hydrochlorothiazide in the geriatric population.

Pregnancy

Telmisartan and hydrochlorothiazide tablets can cause fetal harm when administered to a pregnant woman. The use of drugs that act on the renin-angiotensin system (RAS) during the second and third trimesters of pregnancy is associated with reduced fetal renal function, which can lead to increased fetal and neonatal morbidity and mortality. Therefore, when pregnancy is detected, it is recommended to discontinue telmisartan and hydrochlorothiazide tablets as soon as possible.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown; however, in the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Hypertension during pregnancy poses additional risks, including increased maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications. Furthermore, hypertension can increase the fetal risk for intrauterine growth restriction and intrauterine death.

The use of RAS-active drugs in the second and third trimesters can result in oligohydramnios, reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia, skeletal deformations (including skull hypoplasia), hypotension, and death. In patients taking telmisartan and hydrochlorothiazide tablets during pregnancy, serial ultrasound examinations should be performed to assess the intra-amniotic environment. If oligohydramnios is observed, discontinuation of telmisartan and hydrochlorothiazide tablets is advised unless it is deemed lifesaving for the mother.

Infants with a history of in utero exposure to telmisartan and hydrochlorothiazide tablets should be closely monitored for hypotension, oliguria, and hyperkalemia. Additionally, thiazides, including hydrochlorothiazide, cross the placenta and are associated with risks of fetal or neonatal jaundice, thrombocytopenia, and other adverse reactions that have been observed in adults. Hydrochlorothiazide should not be used to treat hypertension in pregnant women, as it does not prevent or alter the course of edema, proteinuria, and hypertension (EPH) gestosis (pre-eclampsia).

Lactation

There is no information regarding the presence of telmisartan and hydrochlorothiazide tablets or telmisartan in human milk, nor are there data on the effects on breastfed infants or on milk production. Limited published studies indicate that hydrochlorothiazide is present in human milk; however, there is insufficient information to determine its effects on breastfed infants or on milk production.

In animal studies, telmisartan was found in the milk of lactating rats at concentrations 1.5 to 2 times those found in plasma from 4 to 8 hours after administration. Due to the potential for serious adverse reactions in breastfed infants, including hypotension, hyperkalemia, and renal impairment, it is advised that lactating mothers refrain from breastfeeding during treatment with telmisartan and hydrochlorothiazide tablets.

Renal Impairment

Patients with renal impairment should have their renal function and potassium levels monitored closely. This is particularly important for those with reduced kidney function, as they may be at increased risk for complications. Dosing adjustments may be necessary based on the degree of renal impairment to ensure safety and efficacy.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there are no established dosage adjustments, special monitoring requirements, or precautions outlined for individuals with compromised liver function. It is recommended that healthcare providers exercise caution when prescribing this medication to patients with hepatic impairment, given the lack of data on its safety and efficacy in this population. Regular monitoring of liver function may be prudent in these cases, although specific parameters are not defined in the available information.

Overdosage

In cases of overdosage with telmisartan, the most likely manifestations include hypotension, dizziness, and tachycardia. Additionally, bradycardia may occur as a result of parasympathetic (vagal) stimulation. Should symptomatic hypotension arise due to telmisartan overdosage, it is imperative that supportive treatment be initiated promptly to manage the patient's condition effectively.

For hydrochlorothiazide, the most common signs and symptoms associated with overdose are primarily due to electrolyte depletion, which may manifest as hypokalemia, hypochloremia, and hyponatremia, alongside dehydration resulting from excessive diuresis. It is important to note that if digitalis has been co-administered with hydrochlorothiazide, the resultant hypokalemia may exacerbate the risk of cardiac arrhythmias.

The oral LD50 of hydrochlorothiazide has been established to be greater than 10 g/kg in both mice and rats. However, the extent to which hydrochlorothiazide can be removed through hemodialysis remains undetermined. Furthermore, it is critical to recognize that telmisartan is not removed by hemofiltration and is not dialyzable, which underscores the need for careful monitoring and supportive care in cases of overdose.

Nonclinical Toxicology

No teratogenic effects were observed in the studies conducted. In terms of non-teratogenic effects, no drug-related impacts on the reproductive performance of male and female rats were noted at a dose of 100 mg/kg/day, which is approximately 13 times the maximum recommended human dose (MRHD) of telmisartan on a mg/m² basis. This dose resulted in an average systemic exposure to telmisartan that was at least 50 times greater than that observed in humans at the MRHD of 80 mg/day. Additionally, hydrochlorothiazide did not exhibit adverse effects on the fertility of mice and rats of either sex when administered via diet at doses of up to 100 mg/kg and 4 mg/kg, respectively, prior to mating and throughout gestation.

No studies have been conducted to evaluate the carcinogenicity, mutagenicity, or fertility effects of the combination of telmisartan and hydrochlorothiazide. However, telmisartan did not demonstrate evidence of carcinogenicity when administered in the diet to mice and rats for up to two years. The highest doses given to mice (1000 mg/kg/day) and rats (100 mg/kg/day) are approximately 59 and 13 times, respectively, the MRHD of telmisartan. These doses resulted in average systemic exposures to telmisartan that were over 100 times and over 25 times, respectively, the systemic exposure in humans receiving the MRHD.

Genotoxicity assays did not indicate any telmisartan-related effects at the gene or chromosome level. These assays included bacterial mutagenicity tests with Salmonella and E. coli (Ames), a gene mutation test with Chinese hamster V79 cells, a cytogenetic test with human lymphocytes, and a mouse micronucleus test.

Two-year feeding studies conducted by the National Toxicology Program (NTP) found no evidence of carcinogenic potential for hydrochlorothiazide in female mice at doses of up to approximately 600 mg/kg/day or in male and female rats at doses of up to approximately 100 mg/kg/day. However, the NTP did find equivocal evidence for hepatocarcinogenicity in male mice. Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay using various Salmonella typhimurium strains or in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations. In vivo assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene also showed no genotoxicity. Positive results were observed in the in vitro CHO Sister Chromatid Exchange assay, the Mouse Lymphoma Cell mutagenicity assay, and the Aspergillus nidulans non-disjunction assay.

Postmarketing Experience

Postmarketing experience has identified a potential association between the use of telmisartan and hydrochlorothiazide tablets and an increased risk of non-melanoma skin cancer. Patients are advised to take precautions to protect their skin from sun exposure and to undergo regular skin cancer screenings while on this medication.

Patient Counseling

Patients should be advised to read the FDA-approved patient labeling (Patient Information) to understand the medication's uses and potential risks. Female patients of childbearing age should be informed about the consequences of exposure to telmisartan and hydrochlorothiazide tablets during pregnancy. Healthcare providers should discuss treatment options with women who are planning to become pregnant and instruct patients to report any pregnancies to their physicians as soon as possible.

Nursing women should be advised not to breastfeed while undergoing treatment with telmisartan and hydrochlorothiazide tablets. Patients should be made aware that lightheadedness may occur, particularly during the initial days of therapy, and they should report this to their healthcare provider. It is important to inform patients that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to a significant drop in blood pressure, which may result in lightheadedness and possible syncope. Patients should be instructed to contact their healthcare provider if they experience syncope.

Patients should be cautioned against using potassium supplements or salt substitutes containing potassium without first consulting their prescribing healthcare provider. They should also be advised to discontinue telmisartan and hydrochlorothiazide tablets and seek immediate medical attention if they experience symptoms of Acute Myopia or Secondary Angle-Closure Glaucoma.

For those taking hydrochlorothiazide, it is essential to instruct patients to protect their skin from sun exposure and to undergo regular skin cancer screenings.

Storage and Handling

The product is supplied in blister packaging, ensuring the integrity of each tablet until administration. It is essential to store the product at a temperature range of 20°C to 25°C (68°F to 77°F), with permissible excursions between 15°C to 30°C (59°F to 86°F) in accordance with USP Controlled Room Temperature guidelines.

To maintain optimal quality, tablets should remain in their blisters until they are ready to be administered. This practice helps to protect the tablets from moisture and other environmental factors that could compromise their efficacy.

Additional Clinical Information

No further data are available.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Telmisartan and Hydrochlorothiazide as submitted by Glenmark Pharmaceuticals Inc. , USA. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)