Telmisartan/Hydrochlorothiazide

Description

Telmisartan and Hydrochlorothiazide Tablets, USP are a combination of telmisartan, an orally active angiotensin II antagonist targeting the AT1 receptor subtype, and hydrochlorothiazide, a thiazide diuretic. Telmisartan is a non-peptide molecule with the chemical designation 4’-[4-methyl-6-(1-methyl-2-benzimidazolyl)-2-propyl-1-benzimidazolyl methyl]-2-biphenylcarboxylic acid, exhibiting an empirical formula of C33H30N4O2 and a molecular weight of 514.62. It appears as a white or slightly yellowish crystalline powder, is practically insoluble in water, slightly soluble in methanol, sparingly soluble in methylene chloride, and soluble in 1M sodium hydroxide.

Hydrochlorothiazide is characterized as 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, with an empirical formula of C7H8ClN3O4S2 and a molecular weight of 297.74. This compound is a white or practically white, odorless crystalline powder that 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 available for oral administration in three dosage combinations: 40 mg/12.5 mg, 80 mg/12.5 mg, and 80 mg/25 mg of telmisartan and hydrochlorothiazide, respectively. 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 and 80 mg/12.5 mg tablets are colored with ferric oxide red, while the 80 mg/25 mg tablets also include ferric oxide yellow. These tablets are hygroscopic and require protection from moisture. It is noted that FDA-approved dissolution test specifications differ from those of the USP.

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.

Limitations of Use: 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 tolerability, 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. This adjustment is crucial to ensure safety and efficacy in this patient population.

Healthcare professionals should monitor patients closely during the titration process to determine the appropriate dosing that achieves the desired therapeutic effect while minimizing potential adverse reactions.

Contraindications

Use of this product is contraindicated in patients with a known hypersensitivity to telmisartan or any of its components. Additionally, it is contraindicated in individuals with anuria, as the absence of urine production may lead to complications. Co-administration with aliskiren is contraindicated in patients with diabetes due to the potential for 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 informed 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, as this can occur in susceptible individuals. Additionally, renal function and potassium levels should be regularly assessed in patients who may be at risk, ensuring that any potential complications are identified and managed promptly.

Healthcare providers should remain vigilant for clinical signs of fluid or electrolyte imbalance, which may arise during treatment. There is also a risk of hypersensitivity reactions, which necessitates careful monitoring of patients for any adverse effects. Furthermore, patients may experience acute myopia and secondary angle-closure glaucoma, conditions that require immediate attention.

To ensure safe use of telmisartan and hydrochlorothiazide, regular laboratory tests to monitor renal function and potassium levels in susceptible patients are recommended. 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 a significant risk of 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 lead to injury or death of the developing fetus. Therefore, fetal or neonatal exposure should be strictly avoided.

Additional adverse reactions noted in clinical practice include hypersensitivity reactions, acute myopia, and secondary angle-closure glaucoma. It is essential to correct any volume or salt depletion prior to initiating therapy and to monitor for signs and symptoms of hypotension. Renal function and potassium levels should be closely observed in susceptible patients, and clinical signs of fluid or electrolyte imbalance should be monitored.

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 are those resulting from electrolyte depletion, such as hypokalemia, hypochloremia, and hyponatremia, as well as dehydration due to excessive diuresis.

Contraindications for the use of telmisartan and hydrochlorothiazide include hypersensitivity to telmisartan or any of its components, anuria, and co-administration with aliskiren in patients with diabetes.

Drug Interactions

The following drug interactions have been identified, categorized by their pharmacodynamic and pharmacokinetic effects.

Pharmacodynamic Interactions

• Lithium: Co-administration with this medication may increase the risk of lithium toxicity. Monitoring of lithium levels is recommended to avoid adverse effects.

• Non-steroidal Anti-inflammatory Drugs (NSAIDs): The use of NSAIDs may lead to reduced diuretic, natriuretic, and antihypertensive effects. Additionally, there is an increased risk of renal impairment when these agents are used concurrently. Renal function should be monitored in patients receiving both therapies.

• Dual Blockade of the Renin-Angiotensin System: This combination may elevate the risk of renal impairment, hypotension, and hyperkalemia. Patients should be closely monitored for these potential adverse effects.

Pharmacokinetic Interactions

• Antidiabetic Drugs: Dosage adjustments may be necessary when these agents are used in conjunction with the medication. Regular monitoring of blood glucose levels is advised to ensure effective glycemic control.

• Cholestyramine and Colestipol: The absorption of thiazides may be reduced when administered with cholestyramine or colestipol. It is advisable to separate the dosing of these agents to minimize the impact on thiazide absorption.

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. In such cases, exchange transfusions or dialysis may be required to reverse hypotension and/or substitute for disordered renal function.

Geriatric Use

In controlled clinical trials involving 1,017 patients, approximately 20% of those treated with telmisartan/hydrochlorothiazide were aged 65 years or older, with 5% being 75 years of age or older. The data indicate that there were no overall differences in the effectiveness and safety of telmisartan/hydrochlorothiazide in these elderly patients compared to their younger counterparts.

However, while clinical experience has not consistently identified differences in responses between elderly and younger patients, it is important to note that greater sensitivity to the medication in some older individuals cannot be excluded. Therefore, when prescribing telmisartan/hydrochlorothiazide to geriatric patients, careful consideration should be given to dose selection. It is generally recommended to initiate treatment at the lower end of the dosing range. This approach accounts for the increased likelihood of decreased hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies that may affect the patient's response to treatment.

Healthcare providers should remain vigilant in monitoring elderly patients for any potential adverse effects or changes in therapeutic response, ensuring that treatment is both safe and effective.

Pregnancy

Pregnant patients should be advised of the potential consequences of exposure to telmisartan and hydrochlorothiazide tablets during pregnancy. It is important for healthcare providers to discuss treatment options with women who are planning to become pregnant, as the use of these medications may pose risks to fetal outcomes.

Patients are encouraged to report any pregnancies to their physicians as soon as possible to ensure appropriate management and monitoring. For further details, refer to the Warnings and Precautions section (5.1) and the Use in Specific Populations section (8.1) of the prescribing information.

Lactation

Lactating mothers should be advised about the potential consequences of exposure to telmisartan and hydrochlorothiazide tablets during pregnancy. It is important for healthcare providers to discuss treatment options with women who are planning to become pregnant. Additionally, lactating mothers are encouraged to report any pregnancies to their physicians as soon as possible to ensure appropriate management and care. There is no specific data provided regarding the excretion of telmisartan and hydrochlorothiazide in breast milk or their effects on breastfed infants. Therefore, caution is advised when considering the use of this medication in lactating mothers.

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

Limited data are available regarding the overdosage of telmisartan in humans. The most likely manifestations of telmisartan overdosage include hypotension, dizziness, and tachycardia. Additionally, bradycardia may occur due to parasympathetic (vagal) stimulation. In the event of symptomatic hypotension, it is recommended that supportive treatment be initiated.

It is important to note that telmisartan is not removed by hemofiltration and is not dialyzable, which limits the options for removal from the body in cases of overdose.

In contrast, the most common signs and symptoms observed in patients with hydrochlorothiazide overdose are primarily due to electrolyte depletion, including hypokalemia, hypochloremia, and hyponatremia, as well as dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may exacerbate the risk of cardiac arrhythmias.

The extent to which hydrochlorothiazide is removed by hemodialysis has not been established. Furthermore, the oral LD50 of hydrochlorothiazide is greater than 10 g/kg in both mice and rats, indicating a relatively high threshold for acute toxicity in these animal models.

Healthcare professionals should remain vigilant for these symptoms and manage them accordingly in cases of suspected 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 dietary doses of up to 100 mg/kg and 4 mg/kg, respectively, prior to mating and throughout gestation.

No carcinogenicity, mutagenicity, or fertility studies have been conducted with the combination of telmisartan and hydrochlorothiazide. However, telmisartan administration in the diet to mice and rats for up to two years did not reveal any evidence of carcinogenicity. The highest doses administered were 1000 mg/kg/day for mice and 100 mg/kg/day for rats, which correspond to approximately 59 and 13 times the MRHD of telmisartan on a mg/m² basis. 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 either 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 under the National Toxicology Program (NTP) found no evidence of carcinogenic potential for hydrochlorothiazide in female mice at doses up to approximately 600 mg/kg/day or in male and female rats at doses 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 did not show 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

No postmarketing experience details are available in the provided text.

Patient Counseling

Healthcare providers should advise patients to read the FDA-approved patient labeling (Patient Information) thoroughly. This document contains essential information regarding the medication, including its indications, usage, potential side effects, and important safety information. Emphasizing the importance of understanding this material can help patients make informed decisions about their treatment and enhance adherence to prescribed therapies.

Storage and Handling

The product is supplied in blister packs, with specific handling and storage requirements to ensure its integrity and efficacy. It should be stored 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) as defined by USP Controlled Room Temperature guidelines.

To maintain optimal conditions, tablets must remain in their blister packaging until just prior to administration. This practice helps to protect the tablets from moisture and other environmental factors that could compromise their quality.

Additional Clinical Information

Clinicians are advised to monitor renal function periodically in patients whose renal function may be influenced by the renin-angiotensin system, as well as to periodically assess serum electrolytes.

Patients should be counseled to discontinue telmisartan and hydrochlorothiazide tablets immediately upon detection of pregnancy. They should also be informed about the risk of hypersensitivity reactions, particularly those with a history of allergies or bronchial asthma. Additionally, patients should be made aware of the potential for acute transient myopia and acute angle-closure glaucoma, and the necessity to discontinue hydrochlorothiazide if such symptoms arise.

FDA Insert (PDF)

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

View full prescribing information (PDF)