Telmisartan/Hydrochlorothiazide

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 a molecular formula of C33H30N4O2 and a molecular weight of 514.62. It appears as a white to slightly yellowish crystalline powder and is sparingly soluble in methylene chloride, slightly soluble in methanol, and practically insoluble in water, dissolving in 1M sodium hydroxide.

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

Telmisartan and hydrochlorothiazide tablets 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 colloidal silicon dioxide, hydroxypropyl cellulose, lactose monohydrate, mannitol, meglumine, povidone K 30, sodium hydroxide, and sodium stearyl fumarate. The 80 mg/12.5 mg tablets contain ferric oxide red as a coloring agent, while the 40 mg/12.5 mg and 80 mg/25 mg tablets contain ferric oxide yellow. These tablets 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.

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 necessary.

Contraindications

Use of this product is contraindicated in the following situations:

Patients with hypersensitivity to telmisartan or any of its components should not use this medication due to the risk of severe allergic reactions.

The presence of anuria contraindicates use, as the medication requires renal function for efficacy and safety.

Co-administration with aliskiren is contraindicated in patients with diabetes, as this combination may increase the risk of adverse effects.

Warnings and Precautions

When pregnancy is detected, it is imperative to discontinue the use of telmisartan and hydrochlorothiazide as soon as possible due to the risk of fetal toxicity. Medications that directly affect the renin-angiotensin system have the potential to cause injury or death to the developing fetus.

To ensure patient safety, healthcare professionals should take the following precautions:

Fetal and Neonatal Exposure Healthcare providers must avoid fetal or neonatal exposure to this medication.

Volume or Salt Depletion 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, which may arise from the initiation of treatment.

Renal Function and Electrolyte Monitoring Regular monitoring of renal function and potassium levels is recommended, particularly in patients who are susceptible to renal impairment. Additionally, healthcare professionals should observe for clinical signs of fluid or electrolyte imbalance throughout the course of treatment.

Hypersensitivity Reactions Patients should be monitored for any hypersensitivity reactions, which may occur during treatment.

Ocular Effects There is a risk of acute myopia and secondary angle-closure glaucoma associated with the use of this medication. Patients should be informed of these potential ocular effects.

In summary, careful monitoring and management of the aforementioned parameters are crucial for the safe use of telmisartan and hydrochlorothiazide, particularly in vulnerable populations.

Side Effects

Patients receiving telmisartan and hydrochlorothiazide may experience a range of adverse reactions. Common adverse reactions reported include upper respiratory tract infection, dizziness, sinusitis, diarrhea, fatigue, influenza-like symptoms, and nausea.

Serious warnings associated with the use of this medication include 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 and death to the developing fetus. Therefore, avoiding fetal or neonatal exposure is crucial.

Additional important considerations include the need to correct volume or salt depletion prior to initiating therapy, as well as monitoring for signs and symptoms of hypotension. Renal function and potassium levels should be closely monitored in susceptible patients, and clinical signs of fluid or electrolyte imbalance should be observed. Hypersensitivity reactions have also been noted, alongside the potential for acute myopia and secondary angle-closure glaucoma.

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

In cases of overdosage, the most likely manifestations include hypotension, dizziness, and tachycardia, with bradycardia potentially occurring due to parasympathetic (vagal) stimulation. For hydrochlorothiazide overdose, common signs and symptoms are primarily those resulting from electrolyte depletion, such as hypokalemia, hypochloremia, hyponatremia, and 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 in pediatric patients have not been established.

In neonates with a history of in utero exposure to telmisartan and hydrochlorothiazide, 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. 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 careful assessment of the patient's overall health status are essential to ensure safe and effective use of telmisartan/hydrochlorothiazide in this population.

Pregnancy

Telmisartan and hydrochlorothiazide 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, which can lead to oligohydramnios, increased fetal and neonatal morbidity, and even death. Therefore, when pregnancy is detected, it is recommended to discontinue telmisartan and hydrochlorothiazide 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. Hypertension during pregnancy poses additional risks, including increased maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications, as well as increased fetal risk for intrauterine growth restriction and intrauterine death.

In patients who have taken telmisartan and hydrochlorothiazide during pregnancy, serial ultrasound examinations should be performed to assess the intra-amniotic environment. If oligohydramnios is observed, discontinuation of the medication is advised unless it 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 telmisartan and hydrochlorothiazide should be closely monitored for hypotension, oliguria, and hyperkalemia. In cases where oliguria or hypotension occurs, it is essential to support blood pressure and renal perfusion, and interventions such as exchange transfusions or dialysis may be necessary.

Additionally, thiazides, including hydrochlorothiazide, cross the placenta and are associated with risks of fetal or neonatal jaundice, thrombocytopenia, and other adverse reactions. 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, commonly known as pre-eclampsia.

Lactation

There is no information regarding the presence of telmisartan and hydrochlorothiazide 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 has been shown to be present 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 nursing women refrain from breastfeeding during treatment with telmisartan and hydrochlorothiazide.

Renal Impairment

Patients with renal impairment should have their renal function and potassium levels monitored, particularly in those who are susceptible to changes in these parameters. Regular assessment is essential to ensure safe and effective use of the medication in this population.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there is no information available regarding dosage adjustments, special monitoring requirements, or precautions 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.

Overdosage

Overdosage with telmisartan is primarily characterized by hypotension, dizziness, and tachycardia. In some cases, bradycardia may occur due to parasympathetic (vagal) stimulation. Should symptomatic hypotension arise, it is essential to initiate supportive treatment to manage the patient's condition effectively.

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

In instances of hydrochlorothiazide overdose, the predominant signs and symptoms are typically related to 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 further exacerbate the risk of cardiac arrhythmias.

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

Nonclinical Toxicology

No teratogenic effects were observed in the studies conducted. The reproductive performance of male and female rats was unaffected at the highest administered dose of 100 mg/kg/day, which is approximately 13 times the maximum recommended human dose (MRHD) of telmisartan on a mg/m² basis. Additionally, hydrochlorothiazide did not demonstrate adverse effects on the fertility of mice and rats of either sex when administered 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 show evidence of carcinogenicity when administered in the diet to mice and rats for up to two years. Genotoxicity assays indicated no telmisartan-related effects at either the gene or chromosome level. Similarly, two-year feeding studies conducted by the National Toxicology Program (NTP) found no evidence of carcinogenic potential for hydrochlorothiazide in female mice or in male and female rats. Hydrochlorothiazide was also not genotoxic in vitro, as demonstrated by negative results in the Ames mutagenicity assay and the Chinese Hamster Ovary (CHO) test for chromosomal aberrations.

The highest doses administered to mice (1000 mg/kg/day) and rats (100 mg/kg/day) correspond to approximately 59 and 13 times, respectively, 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 observed in humans receiving the MRHD of telmisartan (80 mg/day). In rats, the average systemic exposure during pregnancy (telmisartan AUC on day 6) was at least 50 times greater than that in humans at the MRHD.

The NTP reported equivocal evidence for hepatocarcinogenicity in male mice. Positive 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

No specific postmarketing experience details are available. As such, there are no additional adverse events or rare case reports to summarize at this time.

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 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.

Patients may experience lightheadedness, particularly during the initial days of therapy. They should be instructed to report any instances of lightheadedness 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 advised to contact their healthcare provider if they experience syncope.

Patients should be cautioned against using potassium supplements or salt substitutes that contain potassium without first consulting their prescribing healthcare provider.

Patients must be instructed to discontinue telmisartan and hydrochlorothiazide 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 advise patients to protect their skin from sun exposure and to undergo regular skin cancer screenings.

Storage and Handling

The product is supplied in tablet form, with specific storage conditions 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 quality, tablets must remain in their original bottles or blisters until just prior to administration. This practice helps to protect the tablets from environmental factors that could compromise their stability.

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 Lifestar Pharma LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)