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 diuretic. Telmisartan is a non-peptide molecule with the chemical structure 4’-[(1,4’-dimethyl-2’-propyl2,6’-bi-1H-benzimidazol-1’-yl)methyl]-1,1’-biphenyl-2-carboxylic acid, having an empirical formula of C33H30N4O2 and a molecular weight of 514.63. It appears as a white to slightly yellowish solid, is practically insoluble in water across a pH range of 3 to 9, sparingly soluble in strong acids (except hydrochloric acid), and soluble in strong bases.

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. It is presented as a white or practically white, odorless crystalline powder, slightly soluble in water, and freely soluble in sodium hydroxide solution.

The tablets are formulated for oral administration in three combinations: 40 mg/12.5 mg, 80 mg/12.5 mg, and 80 mg/25 mg of telmisartan and hydrochlorothiazide, respectively. Inactive ingredients include mannitol, sodium hydroxide, meglumine, povidone, sodium stearyl fumarate, lactose monohydrate, and magnesium stearate. The 40 mg/12.5 mg and 80 mg/12.5 mg tablets contain ferric oxide red as a coloring agent, while the 80 mg/25 mg tablets contain ferric oxide yellow. Telmisartan and hydrochlorothiazide tablets are hygroscopic and require protection from moisture.

Uses and Indications

Telmisartan and hydrochlorothiazide tablets, USP are indicated for the treatment of hypertension. This fixed-dose combination is not indicated for initial therapy.

There are no teratogenic or nonteratogenic effects associated with this medication.

Dosage and Administration

The usual starting dose of telmisartan is 40 mg administered once daily. The blood pressure response is dose-related within the range of 20 mg to 80 mg. Hydrochlorothiazide is effective at doses ranging from 12.5 mg to 50 mg, also given once daily. Telmisartan and hydrochlorothiazide tablets may be taken with or without food.

These tablets are available in the following combinations:

• Telmisartan 40 mg and hydrochlorothiazide 12.5 mg

• Telmisartan 80 mg and hydrochlorothiazide 12.5 mg

• Telmisartan 80 mg and hydrochlorothiazide 25 mg

For patients whose blood pressure is not adequately controlled with telmisartan monotherapy at 80 mg, a switch to telmisartan 80 mg/hydrochlorothiazide 12.5 mg once daily may be considered, with the option to titrate up to 160/25 mg if necessary. Conversely, patients inadequately controlled on 25 mg once daily of hydrochlorothiazide may be switched to either telmisartan 80 mg/hydrochlorothiazide 12.5 mg or telmisartan 80 mg/hydrochlorothiazide 25 mg tablets once daily.

The clinical response to telmisartan and hydrochlorothiazide tablets should be evaluated after 2 to 4 weeks of therapy. If blood pressure remains uncontrolled, the dose may be titrated up to 160/25 mg as needed.

Patients with renal impairment may continue the usual regimens of therapy with telmisartan and hydrochlorothiazide tablets, provided that the patient’s creatinine clearance is greater than 30 mL/min. However, these tablets are not recommended for patients with severe hepatic impairment; treatment should be initiated under close medical supervision using the 40/12.5 mg combination.

Contraindications

Telmisartan and hydrochlorothiazide tablets, USP are contraindicated in patients with known hypersensitivity to telmisartan, hydrochlorothiazide, or any other component of this product, including a history of anaphylaxis or angioedema.

The use of this product is also contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs, attributable to the hydrochlorothiazide component.

Additionally, co-administration of aliskiren with telmisartan and hydrochlorothiazide tablets is contraindicated in patients with diabetes.

Warnings and Precautions

The use of telmisartan and hydrochlorothiazide is associated with several critical warnings and precautions that healthcare professionals must consider to ensure patient safety.

Fetal Toxicity The administration of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy poses significant risks, including reduced fetal renal function, increased morbidity, and mortality. Oligohydramnios resulting from such therapy can lead to fetal lung hypoplasia and skeletal deformities. Potential adverse neonatal effects include skull hypoplasia, anuria, hypotension, renal failure, and death. Upon detection of pregnancy, it is imperative to discontinue telmisartan and hydrochlorothiazide as soon as possible. In cases where no suitable alternative therapy exists, healthcare providers must inform the mother of the potential risks to the fetus and conduct serial ultrasound examinations to monitor the intra-amniotic environment. Should oligohydramnios be detected, discontinuation of therapy is advised unless it is deemed lifesaving for the mother.

Risks Associated with Thiazides Hydrochlorothiazide crosses the placental barrier and may appear in cord blood, which raises concerns for fetal or neonatal jaundice, thrombocytopenia, and other adverse reactions similar to those observed in adults. Caution is warranted when initiating antihypertensive therapy in patients with activated renin-angiotensin systems, particularly those who are intravascular volume- or sodium-depleted. These conditions should be corrected prior to the administration of telmisartan and hydrochlorothiazide. Additionally, hydrochlorothiazide should be used cautiously in patients with impaired hepatic function or progressive liver disease, as even minor fluid and electrolyte imbalances may precipitate hepatic coma. Hypersensitivity reactions to hydrochlorothiazide can occur in patients with or without a history of allergy or bronchial asthma, although the risk is heightened in those with such a history. Furthermore, thiazide diuretics have been linked to exacerbation or activation of systemic lupus erythematosus. It is also advised that lithium not be co-administered with thiazides.

Acute Myopia and Secondary Angle-Closure Glaucoma Hydrochlorothiazide may induce an idiosyncratic reaction leading to acute transient myopia and secondary angle-closure glaucoma. Symptoms, which include a sudden decrease in visual acuity or ocular pain, typically manifest within hours to weeks following the initiation of therapy. The primary course of action is to discontinue hydrochlorothiazide immediately.

Monitoring and Emergency Protocols Healthcare providers should perform serial ultrasound examinations to evaluate the intra-amniotic environment in pregnant patients receiving therapy with renin-angiotensin system-affecting drugs. In the event of hypotension, patients should be positioned supine and may require intravenous infusion of normal saline. If oligohydramnios is observed, discontinuation of telmisartan and hydrochlorothiazide is recommended unless the treatment is considered lifesaving for the mother. Additionally, if symptoms of acute angle-closure glaucoma arise, characterized by a sudden decrease in visual acuity or ocular pain, hydrochlorothiazide should be discontinued promptly.

Side Effects

Adverse reactions associated with telmisartan/hydrochlorothiazide (HCTZ) have been observed in clinical trials and post-marketing experiences. The following sections summarize these reactions based on their frequency and seriousness.

Common adverse reactions occurring in 2% or more of patients treated with telmisartan/HCTZ include:

• Central/Peripheral Nervous System: Dizziness (5%).

• Respiratory System Disorders: Upper respiratory tract infection (8%), sinusitis (4%).

• Gastrointestinal System: Diarrhea (3%), nausea (2%).

• Body as a Whole: Fatigue (3%), influenza-like symptoms (2%).

In addition to these common reactions, other adverse events reported at a rate of less than 2% in patients treated with telmisartan/HCTZ, but occurring at a greater rate than in those treated with placebo, include back pain, dyspepsia, vomiting, tachycardia, hypokalemia, bronchitis, pharyngitis, rash, postural hypotension, and abdominal pain. Conversely, reactions such as pain, headache, cough, and urinary tract infection were reported at a rate of 2% or greater in patients treated with telmisartan/HCTZ but were as common or more prevalent in the placebo group.

In controlled trials, 0.3% of patients discontinued treatment due to orthostatic hypotension. The incidence of dizziness was noted to be 4%, 7%, and 1% across different dosages.

Additional adverse reactions associated with telmisartan include:

• Autonomic Nervous System: Impotence, increased sweating, flushing.

• Cardiovascular: Palpitations, dependent edema, angina pectoris, leg edema, abnormal ECG, hypertension, peripheral edema.

• Central Nervous System: Insomnia, somnolence, migraine, vertigo, paresthesia, involuntary muscle contractions, hypoaesthesia.

• Gastrointestinal: Flatulence, constipation, gastritis, dry mouth, hemorrhoids, gastroenteritis, enteritis, gastroesophageal reflux, toothache, and non-specific gastrointestinal disorders.

• Metabolic: Gout, hypercholesterolemia, diabetes mellitus.

• Musculoskeletal: Arthritis, arthralgia, leg cramps, myalgia.

• Psychiatric: Anxiety, depression, nervousness.

• Resistance Mechanism: Infection, fungal infection, abscess, otitis media.

• Respiratory: Asthma, rhinitis, dyspnea, epistaxis.

• Skin: Dermatitis, eczema, pruritus.

• Urinary: Micturition frequency, cystitis.

• Vascular: Cerebrovascular disorder.

• Special Senses: Abnormal vision, conjunctivitis, tinnitus, earache.

A single case of angioedema was reported among a total of 3,781 patients treated with telmisartan.

Adverse reactions associated with hydrochlorothiazide include:

• Body as a Whole: Weakness.

• Digestive: Pancreatitis, jaundice (intrahepatic cholestatic jaundice), sialadenitis, cramping, gastric irritation.

• Hematologic: Aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia.

• Hypersensitivity: Purpura, photosensitivity, urticaria, necrotizing angiitis (vasculitis and cutaneous vasculitis), fever, respiratory distress including pneumonitis and pulmonary edema, anaphylactic reactions.

• Metabolic: Hyperglycemia, glycosuria, hyperuricemia.

• Musculoskeletal: Muscle spasm.

• Nervous System/Psychiatric: Restlessness.

• Renal: Renal failure, renal dysfunction, interstitial nephritis.

• Skin: Erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis.

• Special Senses: Transient blurred vision, xanthopsia.

Post-marketing experience has identified additional adverse reactions, including headache, dizziness, asthenia, coughing, nausea, fatigue, weakness, edema (including face and lower limb), angioneurotic edema, urticaria, hypersensitivity, increased sweating, erythema, chest pain, atrial fibrillation, congestive heart failure, myocardial infarction, increased blood pressure, aggravated hypertension, hypotension (including postural hypotension), hyperkalemia, syncope, dyspepsia, diarrhea, pain, urinary tract infection, erectile dysfunction, back pain, abdominal pain, muscle cramps (including leg cramps), myalgia, bradycardia, eosinophilia, thrombocytopenia, increased uric acid, abnormal hepatic function/liver disorder, renal impairment including acute renal failure, anemia, increased CPK, anaphylactic reactions, and tendon pain (including tendonitis and tenosynovitis). Rare cases of rhabdomyolysis have also been reported in patients receiving angiotensin II receptor blockers, including telmisartan tablets.

Drug Interactions

Co-administration of aliskiren with telmisartan and hydrochlorothiazide tablets is contraindicated in patients with diabetes and those with renal impairment (GFR <60 mL/min).

When telmisartan is used alongside digoxin, there is a notable increase in digoxin plasma concentrations, with median increases of 49% in peak and 20% in trough concentrations. It is advisable to monitor digoxin levels during the initiation, adjustment, and discontinuation of telmisartan to prevent potential over- or under-digitalization.

The concomitant use of lithium with angiotensin II receptor antagonists, including telmisartan, has been associated with reversible increases in serum lithium concentrations and toxicity. Therefore, the combination of lithium with telmisartan and hydrochlorothiazide is not recommended, particularly as lithium should not be used with diuretics.

In elderly patients, those who are volume-depleted, or individuals with compromised renal function, the co-administration of non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors, with telmisartan may lead to renal function deterioration, including possible acute renal failure. These effects are generally reversible; however, renal function should be monitored periodically in patients receiving both telmisartan and NSAID therapy. Additionally, NSAIDs may attenuate the antihypertensive effect of telmisartan.

The combination of telmisartan and ramipril has been shown to increase the steady-state C_max and AUC of ramipril and ramiprilat significantly, while decreasing the C_max and AUC of telmisartan. This interaction may enhance the pharmacodynamic effects of both medications, necessitating careful monitoring of patient response.

Telmisartan has been observed to slightly decrease the mean trough plasma concentration of warfarin without affecting the International Normalized Ratio (INR), indicating that no dosage adjustment is necessary for warfarin when used with telmisartan.

Co-administration of telmisartan with other drugs such as acetaminophen, amlodipine, glibenclamide, simvastatin, hydrochlorothiazide, or ibuprofen does not result in clinically significant interactions. Telmisartan is not metabolized by the cytochrome P450 system and does not significantly affect cytochrome P450 enzymes, except for some inhibition of CYP2C19.

Hydrochlorothiazide may potentiate orthostatic hypotension when used with alcohol, barbiturates, or narcotics. Dosage adjustments of antidiabetic medications may be required when used concurrently. The combination with other antihypertensive drugs may lead to an additive effect.

The absorption of hydrochlorothiazide can be impaired by anionic exchange resins such as cholestyramine and colestipol, which can significantly reduce its gastrointestinal absorption. Co-administration with corticosteroids or ACTH may intensify electrolyte depletion, particularly hypokalemia.

There may be a decreased response to pressor amines when used with hydrochlorothiazide, although this does not preclude their use. Increased responsiveness to nondepolarizing skeletal muscle relaxants may occur.

Due to the risk of lithium toxicity, lithium should generally not be administered with diuretics, including hydrochlorothiazide. Additionally, NSAIDs may reduce the diuretic, natriuretic, and antihypertensive effects of thiazide diuretics, necessitating close observation of the patient to ensure the desired diuretic effect is achieved when these agents are used together.

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

Pediatric patients, particularly neonates with a history of in utero exposure to telmisartan and hydrochlorothiazide, may experience complications such as oliguria or hypotension. In such cases, it is crucial to provide support for blood pressure and renal perfusion. Interventions such as exchange transfusions or dialysis may be necessary to address hypotension and manage impaired renal function.

The safety and effectiveness of this medication in pediatric patients have not been established, indicating a need for caution when considering its use in this population.

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 when comparing elderly patients to their younger counterparts.

While clinical experience has not identified significant differences in responses between geriatric patients and younger individuals, it is important to note that greater sensitivity to the medication may be present in some older adults. Therefore, healthcare providers should exercise caution when prescribing telmisartan/hydrochlorothiazide to elderly patients, considering potential variations in drug response and the need for careful monitoring. No specific dosage adjustments are recommended based solely on age; however, clinicians should remain vigilant in assessing the individual needs and responses of geriatric patients during treatment.

Pregnancy

Pregnant patients should be informed that no carcinogenicity, mutagenicity, or fertility studies have been conducted with the combination of telmisartan and hydrochlorothiazide. Animal studies have shown no drug-related effects on the reproductive performance of male and female rats 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. At this dose, the average systemic exposure to telmisartan (AUC) on day 6 of pregnancy was at least 50 times greater than the average systemic exposure observed in humans at the MRHD of 80 mg/day.

Additionally, hydrochlorothiazide has demonstrated 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, prior to mating and throughout gestation. Given the lack of specific studies on the combination of these agents in pregnant patients, healthcare professionals should weigh the potential benefits against any unknown risks when considering the use of this combination therapy in women who are pregnant or may become pregnant.

Lactation

It is not known whether telmisartan is excreted in human milk; however, it has been demonstrated to be present in the milk of lactating rats. Thiazides are known to appear in human milk.

Due to the potential for adverse effects on the nursing infant, healthcare professionals should consider the importance of the drug to the mother when making a decision to either discontinue nursing or discontinue the medication.

Renal Impairment

Patients with renal impairment do not require specific dosage adjustments based on the available information. Additionally, there are no special monitoring or safety considerations indicated for patients with reduced kidney function.

Hepatic Impairment

Thiazide diuretics should be used with caution in patients with impaired hepatic function or progressive liver disease. In this population, even minor alterations in fluid and electrolyte balance may precipitate hepatic coma. Therefore, careful monitoring of liver function and electrolyte levels is recommended for patients with hepatic impairment. Adjustments to dosage may be necessary based on the severity of liver dysfunction and the patient's clinical status.

Overdosage

Limited data are available regarding overdosage in humans. However, the most likely manifestations of overdosage with telmisartan include 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 removed by hemodialysis, which may influence the management approach in cases of suspected overdosage.

In the context of hydrochlorothiazide overdosage, 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 also been administered, hypokalemia may exacerbate the risk of cardiac arrhythmias, necessitating careful monitoring and management.

The extent to which hydrochlorothiazide is removed by hemodialysis has not been established, which should be taken into consideration when determining the appropriate treatment strategy. Additionally, the oral LD50 of hydrochlorothiazide is greater than 10 g/kg in both mice and rats, indicating a relatively high threshold for toxicity in these animal models.

Nonclinical Toxicology

No carcinogenicity, mutagenicity, or fertility studies have been conducted with the combination of telmisartan and hydrochlorothiazide. However, individual studies on telmisartan have shown no evidence of carcinogenicity when administered in the diet to mice and rats for up to two years. The highest doses administered to mice (1000 mg/kg/day) and rats (100 mg/kg/day) are approximately 59 and 13 times, respectively, the maximum recommended human dose (MRHD) of telmisartan. These doses have resulted in average systemic exposures to telmisartan that are greater than 100 times and 25 times, respectively, the systemic exposure observed in humans receiving the MRHD of 80 mg/day.

Genotoxicity assays conducted on telmisartan did not reveal any 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. Additionally, no drug-related effects on the reproductive performance of male and female rats were noted at the highest administered dose of 100 mg/kg/day, which is about 13 times the MRHD of telmisartan on a mg/m² basis. This dose resulted in an average systemic exposure (telmisartan AUC as determined on day 6 of pregnancy) that was at least 50 times the average systemic exposure in humans at the MRHD.

Two-year feeding studies conducted under the auspices of 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 and in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations, nor in vivo in assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene.

Positive test results were obtained in the in vitro CHO Sister Chromatid Exchange (clastogenicity) assay, the Mouse Lymphoma Cell (mutagenicity) assay, and the Aspergillus nidulans non-disjunction assay. Hydrochlorothiazide also demonstrated no adverse effects on the fertility of mice and rats of either sex in studies where these species were exposed, via their diet, to doses of up to 100 mg/kg and 4 mg/kg, respectively, prior to mating and throughout gestation.

Postmarketing Experience

During post-approval use of telmisartan tablets, various adverse reactions have been identified. These reactions have been reported voluntarily from a population of uncertain size, making it challenging to reliably estimate their frequency or establish a causal relationship to drug exposure. The inclusion of these reactions in labeling is typically based on factors such as the seriousness of the reaction, frequency of reporting, and the strength of the causal connection to telmisartan tablets.

The most frequently reported events include headache, dizziness, asthenia, coughing, nausea, fatigue, weakness, edema (including face and lower limb edema), angioneurotic edema, urticaria, hypersensitivity, increased sweating, erythema, chest pain, atrial fibrillation, congestive heart failure, myocardial infarction, increased blood pressure, aggravated hypertension, hypotension (including postural hypotension), hyperkalemia, syncope, dyspepsia, diarrhea, pain, urinary tract infection, erectile dysfunction, back pain, abdominal pain, muscle cramps (including leg cramps), myalgia, bradycardia, eosinophilia, thrombocytopenia, increased uric acid, abnormal hepatic function or liver disorder, renal impairment (including acute renal failure), anemia, increased CPK, anaphylactic reactions, tendon pain (including tendonitis and tenosynovitis), drug eruptions (primarily reported as toxic skin eruptions, rash, and urticaria), hypoglycemia (in diabetic patients), and angioedema, which has been associated with fatal outcomes.

Additionally, rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers, including telmisartan tablets.

Patient Counseling

Healthcare providers should advise patients that if pregnancy is detected, telmisartan and hydrochlorothiazide should be discontinued as soon as possible. It is important to inform female patients of childbearing age about the potential consequences of exposure to these medications during pregnancy. Providers should discuss alternative treatment options with women who are planning to become pregnant and encourage patients to report any pregnancies to their physicians promptly.

Patients receiving telmisartan and hydrochlorothiazide tablets should be cautioned about the possibility of lightheadedness, particularly during the initial days of therapy. They should be instructed to report any instances of lightheadedness to their prescribing physician. In cases of syncope, patients must discontinue the medication and consult their physician before resuming treatment.

Additionally, all patients should be made aware that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to a significant drop in blood pressure, which may result in lightheadedness or syncope.

Patients should also be informed not to use potassium supplements or salt substitutes containing potassium without first consulting their prescribing physician.

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° to 25°C (68° to 77°F), with permissible excursions between 15° to 30°C (59° to 86°F).

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

Additional Clinical Information

Telmisartan and hydrochlorothiazide tablets can be administered with or without food. Clinicians should counsel female patients of childbearing age about the potential risks associated with exposure to these medications during pregnancy and discuss alternative treatment options for those planning to conceive. Patients are advised to promptly report any pregnancies to their healthcare provider.

Patients should be informed that lightheadedness may occur, particularly during the initial days of therapy, and should report this to their physician. In cases of syncope, the medication should be discontinued until medical advice is obtained. Additionally, patients must be cautioned that inadequate fluid intake, excessive sweating, diarrhea, or vomiting can lead to significant drops in blood pressure, resulting in lightheadedness or syncope. It is also important for patients to avoid potassium supplements or salt substitutes containing potassium unless directed by their physician.

Postmarketing experience has revealed various adverse reactions associated with telmisartan tablets, including headache, dizziness, and fatigue, as well as more serious effects such as hypotension, hyperkalemia, and renal impairment. Rare instances of rhabdomyolysis have been reported among patients using angiotensin II receptor blockers, including telmisartan.

FDA Insert (PDF)

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

View full prescribing information (PDF)