Hydrochlorothiazide/Telmisartan

Description

Telmisartan and hydrochlorothiazide tablets USP are a combination of telmisartan, an orally active angiotensin II antagonist, and hydrochlorothiazide, a thiazide diuretic. Telmisartan is chemically described as 4'-[(1, 4'-dimethyl-2'-propyl2,6'-bi-1H-benzimidazol-1'-yl)methyl]-1,1'-biphenyl-2-carboxylic acid, with an empirical formula of C33H30N4O2 and a molecular weight of 514.63. It appears as a white to slightly yellowish solid and is practically insoluble in water, sparingly soluble in strong acid (except insoluble in hydrochloric acid), and soluble in strong base.

Hydrochlorothiazide is chemically described 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. It is a white, or practically white, practically odorless, crystalline powder that is slightly soluble in water and freely soluble in sodium hydroxide solution.

Telmisartan and hydrochlorothiazide tablets USP are formulated for oral administration in strengths of 40 mg/12.5 mg, 80 mg/12.5 mg, and 80 mg/25 mg. The tablets contain inactive ingredients including crosscarmalose sodium, lactose monohydrate, magnesium stearate, povidone, and sodium hydroxide. The 40 mg/12.5 mg and 80 mg/12.5 mg tablets contain red iron oxide as a coloring agent, while the 80 mg/25 mg tablets contain yellow iron oxide.

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.

These tablets are not indicated for initial therapy. There are no teratogenic or nonteratogenic effects associated with the use of this medication.

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. It is also contraindicated in individuals with anuria, as the absence of urine production may lead to complications. Additionally, 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 tablets. It is imperative that these medications be discontinued as soon as pregnancy is detected, as drugs that act directly on the renin-angiotensin system may cause injury or death to the developing fetus. Healthcare professionals should 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 such occurrences. Furthermore, there is a risk of acute myopia and secondary angle-closure glaucoma, which necessitates careful observation and management.

To ensure safe use of telmisartan and hydrochlorothiazide tablets, healthcare professionals should conduct laboratory tests to monitor renal function and potassium levels in susceptible patients. This proactive approach will help mitigate risks and enhance patient safety during treatment.

Side Effects

Patients receiving telmisartan and hydrochlorothiazide tablets 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 the use of these medications include the potential for fetal toxicity. It is imperative that telmisartan and hydrochlorothiazide tablets be discontinued as soon as pregnancy is detected, as drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. Therefore, fetal or neonatal exposure should be avoided.

Additional adverse reactions noted in clinical practice include hypersensitivity reactions, acute myopia, and secondary angle-closure glaucoma. Patients should be monitored for signs and symptoms of hypotension, particularly if there is a history of volume or salt depletion prior to initiating therapy. Renal function and potassium levels should also be monitored in susceptible patients, and clinical signs of fluid or electrolyte imbalance should be observed.

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.

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

There are currently no documented drug interactions associated with this medication. Additionally, there are no known interactions with laboratory tests. As such, no specific recommendations for dosage adjustments or monitoring are necessary 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. 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, approximately 20% of patients treated with telmisartan/hydrochlorothiazide were aged 65 years or older, with 5% being 75 years of age or older. Overall, no significant differences in effectiveness and safety were observed between elderly patients and younger patients. However, it is important to note that greater sensitivity to the medication may be present in some older individuals.

When prescribing telmisartan/hydrochlorothiazide to geriatric patients, dose selection should be approached with caution. It is generally recommended to initiate treatment at the lower end of the dosing range. This recommendation is based on the increased likelihood of decreased hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies in this population. Careful monitoring of these patients is advised to ensure safety and efficacy.

Pregnancy

Telmisartan and hydrochlorothiazide tablets can cause fetal harm when administered to pregnant patients. 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, leading to increased morbidity and mortality in both the fetus and neonate. Most epidemiologic studies examining fetal abnormalities following antihypertensive use in the first trimester have not differentiated between RAS-affecting drugs and other antihypertensive agents.

Animal studies have demonstrated fetotoxicity with telmisartan only at maternally toxic doses. 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 in the general U.S. population is 2% to 4% and 15% to 20%, respectively; however, the specific background risk for the indicated population remains unknown. All pregnancies carry a background risk of birth defects, loss, or other adverse outcomes.

Hypertension during pregnancy poses additional risks, including increased maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications. Fetal risks associated with maternal hypertension include intrauterine growth restriction and intrauterine death. Therefore, pregnant women with hypertension should be closely monitored and managed appropriately.

The use of RAS-affecting drugs in the second and third trimesters can lead to oligohydramnios, reduced fetal renal function resulting in anuria and renal failure, fetal lung hypoplasia, skeletal deformations (including skull hypoplasia), hypotension, and death. In cases where there is no suitable alternative therapy, healthcare providers should inform the mother of the potential risks to the fetus. For patients taking telmisartan and hydrochlorothiazide tablets during pregnancy, serial ultrasound examinations should be performed to assess the intra-amniotic environment, and fetal testing may be warranted based on gestational age.

If oligohydramnios is detected, discontinuation of telmisartan and hydrochlorothiazide tablets is advised unless the treatment is deemed lifesaving for the mother. It is important to note that oligohydramnios may not manifest until after the fetus has sustained irreversible injury. Infants with a history of in utero exposure to these medications should be closely monitored for hypotension, oliguria, and hyperkalemia. In cases of oliguria or hypotension, supportive measures for blood pressure and renal perfusion may be necessary, and interventions such as exchange transfusions or dialysis could be required.

Thiazides, including hydrochlorothiazide, cross the placenta and are associated with risks of fetal or neonatal jaundice, thrombocytopenia, and other adverse reactions. Hydrochlorothiazide, like other diuretics, may cause placental hypoperfusion and 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). Additionally, the use of hydrochlorothiazide for other indications, such as heart disease, during pregnancy should be avoided.

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, limited data are available regarding its effects in humans. The most likely manifestations include hypotension, dizziness, and tachycardia. Additionally, bradycardia may occur due to parasympathetic (vagal) stimulation.

Should symptomatic hypotension arise, it is imperative that supportive treatment be initiated to manage the condition effectively. It is important to note that telmisartan is not removed by hemofiltration and is not dialyzable, which limits the options for intervention in cases of significant overdosage.

In the context of hydrochlorothiazide overdose, the predominant signs and symptoms are typically associated with electrolyte depletion, including hypokalemia, hypochloremia, and hyponatremia, as well as dehydration resulting from excessive diuresis. If digitalis has been co-administered, the presence of hypokalemia may exacerbate the risk of cardiac arrhythmias, necessitating careful monitoring and management.

The oral LD50 of hydrochlorothiazide has been established as greater than 10 g/kg in both mice and rats, indicating a high threshold for acute toxicity in these animal models. Healthcare professionals should remain vigilant for these potential complications and manage them accordingly.

Nonclinical Toxicology

No teratogenic effects have been identified in the studies conducted. Additionally, there were no adverse effects on the fertility of mice and rats of either sex when exposed to doses of up to 100 mg/kg and 4 mg/kg, respectively, via their diet prior to mating and throughout gestation.

No carcinogenicity, mutagenicity, or fertility studies have been performed with the combination of telmisartan and hydrochlorothiazide. However, when telmisartan was administered in the diet to mice and rats for up to two years, there was no evidence of carcinogenicity. Genotoxicity assays also did not indicate any telmisartan-related effects at either the gene or chromosome level. Furthermore, no drug-related effects on the reproductive performance of male and female rats were observed at a dose of 100 mg/kg/day.

In two-year feeding studies, hydrochlorothiazide did not demonstrate any evidence of carcinogenic potential in female mice or in male and female rats. Hydrochlorothiazide was found to be non-genotoxic in vitro in the Ames mutagenicity assay and in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations. However, positive test results were obtained 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 symptom 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 various package configurations, with specific NDC numbers available upon request. It should be stored at a controlled room temperature of 25°C (77°F). Temporary excursions are permissible within the range of 15 to 30°C (59 to 86°F), in accordance with USP guidelines for controlled room temperature. Proper storage conditions are essential to maintain the integrity and efficacy of the product.

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 Lupin Pharmaceuticals, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)