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'-[(1,4'-dimethyl-2'-propyl2,6'-bi-1H-benzimidazol-1'-yl)methyl]-1,1'-biphenyl-2-carboxylic acid, exhibiting a molecular formula of C33H30N4O2 and a molecular weight of 514.63. It appears as a white or slightly yellowish crystalline powder, is sparingly soluble in methylene chloride, slightly soluble in methanol, and practically insoluble in water, but dissolves in 1M sodium hydroxide.

Hydrochlorothiazide is chemically defined 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. This compound is presented as a white or practically white, practically odorless crystalline powder, 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, hydroxypropyl cellulose, lactose monohydrate, mannitol, meglumine, povidone, sodium hydroxide pellets, and sodium stearyl fumarate. The 40 mg/12.5 mg and 80 mg/12.5 mg formulations include red ferric oxide, while the 80 mg/25 mg formulation contains yellow ferric oxide. These tablets are hygroscopic and require protection from moisture, and they meet USP dissolution test 3.

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. Careful monitoring of the patient's condition is advised during the titration process to ensure optimal therapeutic outcomes while minimizing potential adverse effects.

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.

Anuria is a contraindication, as the absence of urine production may indicate severe renal impairment, which could be exacerbated by this treatment.

Co-administration with aliskiren is contraindicated in patients with diabetes, as this combination may increase the risk of adverse effects related to renal function and blood pressure regulation.

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 in the developing fetus. Healthcare professionals should be vigilant in avoiding fetal or neonatal exposure to these agents.

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. Regular assessment of renal function and potassium levels is recommended, particularly in patients who may be at increased risk. Additionally, healthcare providers should remain alert for clinical signs of fluid or electrolyte imbalance, which may necessitate intervention.

Hypersensitivity reactions have been reported and should be taken into consideration when prescribing these medications. Furthermore, patients may experience acute myopia and secondary angle-closure glaucoma, which require immediate attention.

To ensure safe use, it is crucial to conduct laboratory tests that monitor renal function and potassium levels in susceptible patients. This proactive approach will help mitigate potential risks associated with the therapy.

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 Fetal Toxicity. It is imperative to discontinue telmisartan and hydrochlorothiazide 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. Patients should avoid fetal or neonatal exposure, and it is essential to correct any volume or salt depletion prior to initiating therapy. Clinicians should monitor for signs and symptoms of hypotension, renal function, and potassium levels in susceptible patients, as well as observe for clinical signs of fluid or electrolyte imbalance.

Additional adverse reactions may include hypersensitivity reactions, acute myopia, secondary angle-closure glaucoma, anuria, and hypersensitivity to telmisartan or any of its components. Co-administration with aliskiren in patients with diabetes is also cautioned against.

In cases of overdosage, the most likely manifestations with telmisartan include hypotension, dizziness, and tachycardia, while bradycardia may occur 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. If digitalis has been administered concurrently, hypokalemia may exacerbate cardiac arrhythmias.

Fetal and neonatal adverse reactions associated with the use of drugs acting on the renin-angiotensin system during the second and third trimesters of pregnancy can include oligohydramnios, reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia, skeletal deformations (including skull hypoplasia), hypotension, and death. Additionally, thiazides can cross the placenta, and their use during pregnancy is linked to risks of fetal or neonatal jaundice, thrombocytopenia, and other adverse reactions that have been observed in adults.

Drug Interactions

The following drug interactions have been identified, categorized by their pharmacological effects and mechanisms:

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

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) The use of NSAIDs may lead to a reduction in the diuretic, natriuretic, and antihypertensive effects of the medication. Additionally, there is an increased risk of renal impairment when NSAIDs are used concurrently. It is advisable to monitor renal function and consider alternative analgesics if necessary.

Renin-Angiotensin System Blockers When used in conjunction with agents that cause dual blockade of the renin-angiotensin system, there is an elevated risk of renal impairment, hypotension, and hyperkalemia. Close monitoring of blood pressure, renal function, and serum potassium levels is recommended.

Antidiabetic Drugs Patients taking antidiabetic medications may require dosage adjustments to maintain glycemic control. Regular monitoring of blood glucose levels is advised to ensure appropriate management.

Cholestyramine and Colestipol The concomitant use of cholestyramine or colestipol may result in reduced absorption of thiazide diuretics. It is recommended to separate the administration of these agents to minimize the impact on thiazide efficacy.

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 involving 1,017 patients, approximately 20% of those treated with telmisartan/hydrochlorothiazide were aged 65 years or older, with 5% being 75 years 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 ruled out. Therefore, dose selection for geriatric patients should be approached with caution. It is generally recommended to initiate treatment at the lower end of the dosing range, taking into account the increased likelihood of decreased hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies.

Healthcare providers should closely monitor elderly patients for any adverse effects and adjust dosages as necessary to ensure safety and efficacy 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, leading to oligohydramnios, increased fetal and neonatal morbidity, and potential death. Epidemiologic studies examining fetal abnormalities following antihypertensive use in the first trimester have not specifically distinguished RAS-affecting drugs from 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 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, although the specific background risk for the indicated population remains unknown.

Hypertension during pregnancy poses increased maternal risks, including pre-eclampsia, gestational diabetes, premature delivery, and delivery complications. Additionally, it increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be closely monitored and managed accordingly.

In cases where there is no appropriate alternative to therapy with RAS-affecting drugs, healthcare providers should inform the mother of the potential risks to the fetus. Serial ultrasound examinations are advised for patients taking telmisartan and hydrochlorothiazide during pregnancy to assess the intra-amniotic environment. If oligohydramnios is observed, discontinuation of the medication is warranted 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 observed for hypotension, oliguria, and hyperkalemia. In the event of oliguria or hypotension, supportive measures for blood pressure and renal perfusion may be necessary, including potential exchange transfusions or dialysis. Thiazides, including hydrochlorothiazide, cross the placenta and are associated with risks of fetal or neonatal jaundice, thrombocytopenia, and other adverse reactions. Therefore, the use of hydrochlorothiazide for indications such as heart disease during pregnancy should be avoided, as these medications do not prevent or alter the course of edema, proteinuria, and hypertension (EPH) gestosis (pre-eclampsia).

Lactation

Lactating mothers should be closely observed for any adverse effects in breastfed infants who have been exposed in utero to telmisartan and hydrochlorothiazide. Infants may be at risk for hypotension, oliguria, and hyperkalemia. In cases where oliguria or hypotension is observed, it is essential to support blood pressure and renal perfusion, and interventions such as exchange transfusions or dialysis may be necessary to reverse hypotension and restore renal function.

It is important to note that thiazides, including hydrochlorothiazide, can cross the placenta, with concentrations in the umbilical vein approaching those found in maternal plasma. Hydrochlorothiazide may also lead to placental hypoperfusion and can accumulate in amniotic fluid, with reported concentrations up to 19 times higher than those in umbilical vein plasma. The use of thiazides during pregnancy has been associated with risks such as fetal or neonatal jaundice and thrombocytopenia. Therefore, healthcare professionals should exercise caution and monitor breastfed infants accordingly.

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 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 should be considered when managing an overdose situation.

In cases of hydrochlorothiazide overdose, the predominant signs and symptoms are typically those associated with 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.

The oral LD50 of hydrochlorothiazide has been determined to be 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 symptoms and manage accordingly.

Nonclinical Toxicology

No teratogenic effects were observed in the studies conducted. The combination of telmisartan and hydrochlorothiazide has not been evaluated for carcinogenicity, mutagenicity, or fertility. However, individual studies on telmisartan indicated no evidence of carcinogenicity when administered in the diet to mice and rats for up to two years. Genotoxicity assays for telmisartan did not demonstrate any effects at either the gene or chromosome level.

In terms of reproductive performance, no drug-related effects were noted in male and female rats at a dose of 100 mg/kg/day. Similarly, two-year feeding studies with hydrochlorothiazide revealed no evidence of carcinogenic potential in female mice or in male and female rats. Hydrochlorothiazide was also found to be non-genotoxic in vitro, as demonstrated by the Ames mutagenicity assay and the Chinese Hamster Ovary (CHO) test for chromosomal aberrations.

Furthermore, hydrochlorothiazide did not adversely affect the fertility of mice and rats of either sex in studies where these species were exposed to doses of up to 100 mg/kg and 4 mg/kg, respectively.

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

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 manage their health effectively.

Storage and Handling

The product is supplied in blister packs, with specific handling requirements to ensure optimal quality. It is essential to store the tablets at a temperature range of 20° to 25°C (68° to 77°F), in accordance with USP Controlled Room Temperature guidelines.

To maintain the integrity of the tablets, they should remain in their blister packaging until just prior to administration. This practice helps to protect the tablets from environmental factors that may affect their efficacy.

Additional Clinical Information

Clinicians are advised to monitor renal function periodically in patients whose renal function may be influenced by the activity of the renin-angiotensin system. Additionally, it is important to periodically assess serum electrolytes to ensure patient safety and optimal therapeutic outcomes.

FDA Insert (PDF)

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

View full prescribing information (PDF)