Twynsta

If you take too much Twynsta, call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

• StoreTwynsta between 59° to 86°F (15° to 30°C).
• Do not remove Twynsta from blisters until right before you take them.
• Keep Twynsta out of the light and away from moisture.
• Keep Twynsta and all medicines out of the reach of children.

Amlodipine is a calcium channel blocker. Amlodipine relaxes (widens) blood vessels and improves blood flow.

Telmisartan is an angiotensin II receptor antagonist. Telmisartan keeps blood vessels from narrowing, which lowers blood pressure and improves blood flow.

Amlodipine and telmisartan is a combination medicine used to treat high blood pressure (hypertension). Lowering blood pressure may lower your risk of a stroke or heart attack.

Amlodipine and telmisartan may also be used for purposes not listed in this medication guide.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Bloating or swelling of the face, arms, hands, lower legs, or feet
• body aches or pain
• chills
• cough
• difficulty breathing
• ear congestion
• fever
• headache
• loss of voice
• nasal congestion
• rapid weight gain
• runny nose
• sneezing
• sore throat
• tingling of the hands or feet
• unusual tiredness or weakness
• unusual weight gain or loss

• Bladder pain
• bloody or cloudy urine
• blurred vision
• chest pain
• diarrhea
• difficult, burning, or painful urination
• dizziness
• frequent urge to urinate
• general feeling of discomfort or illness
• joint pain
• loss of appetite
• lower back or side pain
• muscle aches and pains
• nausea
• nervousness
• pounding in the ears
• shivering
• slow or fast heartbeat
• sweating
• trouble sleeping
• vomiting

• Abdominal or stomach pain
• arm, back, or jaw pain
• black, tarry stools
• bleeding gums
• blistering, peeling, or loosening of the skin
• blood in the urine or stools
• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• chest tightness or heaviness
• cold sweats
• confusion
• constipation
• cough or hoarseness
• dark urine
• difficult or labored breathing
• difficulty swallowing
• dry mouth
• extreme fatigue
• fast, irregular, pounding, or racing heartbeat or pulse
• feeling of warmth
• flushed, dry skin
• fruit-like breath odor
• hives
• increased hunger
• increased sweating
• increased thirst
• increased volume of pale, dilute urine
• irregular heartbeat
• irritation in the mouth
• joint or muscle pain
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• lightheadedness, dizziness, or fainting
• loss of consciousness
• muscle cramps or stiffness
• pale, bluish-colored, or cold hands or feet
• pinpoint red spots on the skin
• rash
• redness and swelling of the gums
• redness, soreness, or itching skin
• severe or sudden headache
• sudden loss of coordination
• sudden slurring of speech
• swollen glands
• tightness in the chest
• trembling or shaking of the hands or feet
• unexplained weight loss
• unusual bleeding or bruising
• vomiting of blood
• weakness in the arms, hands, legs, or feet
• weight gain
• yellow eyes or skin

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Acid or sour stomach
• belching
• difficulty with moving
• heartburn
• indigestion
• pain or tenderness around the eyes and cheekbones
• sleepiness or unusual drowsiness

• Abnormal dreams
• ankle, knee, or great toe joint pain
• anxiety
• bad, unusual, or unpleasant (after) taste
• bleeding after defecation
• blistering, crusting, irritation, itching, or reddening of the skin
• bloody nose
• burning feeling in the chest or stomach
• burning, dry, or itching eyes
• changes in vision
• cold and clammy skin
• continuing ringing or buzzing or other unexplained noise in the ears
• cough producing mucus
• cracked, dry, or scaly skin
• decreased sexual performance or desire
• depression
• dry mouth
• earache
• excess air or gas in the stomach or intestines
• feeling of constant movement of self or surroundings
• feeling of warmth
• full feeling
• hair loss or thinning of the hair
• headache, severe and throbbing
• hearing loss
• hives or welts
• hyperventilation
• inability to have or keep an erection
• increased appetite
• irritability
• lack of feeling or emotion
• lack or loss of strength
• loose stools
• loss of memory
• redness of the skin
• redness or swelling in the ear
• redness, pain, or swelling of the eye, eyelid, or inner lining of the eyelid
• restlessness
• tenderness in the stomach area
• toothache
• uncomfortable swelling around the anus

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

• It is used to treat high blood pressure.

• Tell all of your health care providers that you take Twynsta. This includes your doctors, nurses, pharmacists, and dentists.
• Avoid driving and doing other tasks or actions that call for you to be alert until you see how this medicine affects you.
• To lower the chance of feeling dizzy or passing out, rise slowly if you have been sitting or lying down. Be careful going up and down stairs.
• Have your blood pressure checked often. Talk with your doctor.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• It is rare, but worse chest pain and heart attack can happen after Twynsta is first started or after the dose is raised. The risk may be greater in people who have very bad heart blood vessel disease. Talk with the doctor.
• It may take a few weeks to see the full effect.
• Talk with your doctor before using OTC products that may raise blood pressure. These include cough or cold drugs, diet pills, stimulants, ibuprofen or like products, and some natural products or aids.
• If you are taking a salt substitute that has potassium, potassium-sparing diuretics, or potassium, talk with your doctor.
• If you are on a low-salt or salt-free diet, talk with your doctor.
• Talk with your doctor before you drink alcohol.
• Be careful in hot weather or while being active. Drink lots of fluids to stop fluid loss.
• Tell your doctor if you have too much sweat, fluid loss, throwing up, or loose stools. This may lead to low blood pressure.
• This medicine may affect how much of some other drugs are in your body. If you are taking other drugs, talk with your doctor. You may need to have your blood work checked more closely while taking this medicine with your other drugs.
• If you are 65 or older, use Twynsta with care. You could have more side effects.

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Take with or without food.
• Do not take Twynsta out of the blister pack until you are ready to take it. Take this medicine right away after opening the blister pack. Do not store the removed drug for future use.
• Keep taking Twynsta as you have been told by your doctor or other health care provider, even if you feel well.
• Take this medicine at the same time of day.
• To gain the most benefit, do not miss doses.
• Drink lots of noncaffeine liquids unless told to drink less liquid by your doctor.

What do I do if I miss a dose?

• Take a missed dose as soon as you think about it.
• If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of kidney problems like unable to pass urine, change in how much urine is passed, blood in the urine, or a big weight gain.
• Signs of a high potassium level like a heartbeat that does not feel normal; change in thinking clearly and with logic; feeling weak, lightheaded, or dizzy; feel like passing out; numbness or tingling; or shortness of breath.
• Very bad dizziness or passing out.
• Chest pain or pressure or a fast heartbeat.
• A heartbeat that does not feel normal.
• Shortness of breath, a big weight gain, or swelling in the arms or legs.
• Stiff muscles, shakiness, or muscle movements that are not normal.

• Store in the original container at room temperature.
• Protect from light.
• Store in a dry place. Do not store in a bathroom.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

Twynsta (telmisartan/amlodipine) tablets are indicated for the treatment of hypertension, alone or with other antihypertensive agents to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including angiotensin II receptor blockers and dihydropyridine calcium channel blockers. There are no controlled trials demonstrating risk reduction with Twynsta.

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.

Twynsta tablets may also be used as initial therapy in patients who are likely to need multiple drugs to achieve their blood pressure goals.

Base the choice of Twynsta tablets as initial therapy for hypertension on an assessment of potential benefits and risks including whether the patient is likely to tolerate the starting dose of Twynsta tablets.

Patients with moderate or severe hypertension are at relatively high risk for cardiovascular events (such as strokes, heart attacks, and heart failure), kidney failure, and vision problems, so prompt treatment is clinically relevant. Consider the patient's baseline blood pressure, the target goal, and the incremental likelihood of achieving goal with a combination compared with monotherapy when deciding whether to use Twynsta tablets as initial therapy. Individual blood pressure goals may vary based upon the patient’s risk.

Data from an 8-week, placebo-controlled, multidose, factorial trial provide estimates of the probability of reaching a blood pressure goal with Twynsta compared to telmisartan or amlodipine monotherapy and placebo [see Clinical Studies (14.1)].

The figures below provide estimates of the likelihood of achieving systolic and diastolic blood pressure control with Twynsta 80/10 mg tablets, based upon baseline systolic or diastolic blood pressure. The curve of each treatment group was estimated by logistic regression modeling. The estimated likelihood at the right tail of each curve is less reliable due to small numbers of subjects with high baseline blood pressures.

Figure 1a: Probability of Achieving Systolic Blood Pressure <140 mmHg at Week 8

Figure 1b: Probability of Achieving Systolic Blood Pressure <130 mmHg at Week 8

Figure 2a: Probability of Achieving Diastolic Blood Pressure <90 mmHg at Week 8

Figure 2b: Probability of Achieving Diastolic Blood Pressure <80 mmHg at Week 8

The figures above provide an approximation of the likelihood of reaching a targeted blood pressure goal at 8 weeks. For example, a patient with a baseline blood pressure of 160/110 mmHg has about a 16% likelihood of achieving a goal of <140 mmHg (systolic) and 16% likelihood of achieving <90 mmHg (diastolic) on placebo. The likelihood of achieving these same goals on telmisartan is about 46% (systolic) and 26% (diastolic). The likelihood of achieving these same goals on amlodipine is about 69% (systolic) and 22% (diastolic). These likelihoods rise to 79% for systolic and 55% for diastolic with Twynsta.

Telmisartan
Limited data are available with regard to overdosage in humans. The most likely manifestations of overdosage with telmisartan tablets would be hypotension, dizziness, and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be instituted. Telmisartan is not removed by hemodialysis.

Amlodipine
Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly a reflex tachycardia. In humans, experience with intentional overdosage of amlodipine is limited.

Single oral doses of amlodipine maleate equivalent to 40 mg amlodipine/kg and 100 mg amlodipine/kg in mice and rats, respectively, caused deaths. Single oral amlodipine maleate doses equivalent to 4 or more mg amlodipine/kg or higher in dogs (11 or more times the maximum recommended human dose on a mg/m2 basis) caused a marked peripheral vasodilation and hypotension.

If massive overdose should occur, initiate active cardiac and respiratory monitoring. Frequent blood pressure measurements are essential. Should hypotension occur, provide cardiovascular support including elevation of the extremities and the judicious administration of fluids. If hypotension remains unresponsive to these conservative measures, consider administration of vasopressors (such as phenylephrine) with attention to circulating volume and urine output. As amlodipine is highly protein bound, hemodialysis is not likely to be of benefit.

  Carcinogenesis, Mutagenesis, Impairment of Fertility

Telmisartan
There was no evidence of carcinogenicity when telmisartan was administered in the diet to mice and rats for up to 2 years. The highest doses administered to mice (1000 mg/kg/day) and rats (100 mg/kg/day) are, on a mg/m2 basis, about 59 and 13 times, respectively, the maximum recommended human dose (MRHD) of telmisartan. These same doses have been shown to provide average systemic exposures to telmisartan >100 times and >25 times, respectively, the systemic exposure in humans receiving the MRHD (80 mg/day).

Genotoxicity assays did not reveal 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.

No drug-related effects on the reproductive performance of male and female rats were noted at 100 mg/kg/day (the highest dose administered), about 13 times, on a mg/m2 basis, the MRHD of telmisartan. This dose in the rat resulted in an average systemic exposure (telmisartan AUC as determined on day 6 of pregnancy) at least 50 times the average systemic exposure in humans at the MRHD (80 mg/day).

Amlodipine
Rats and mice treated with amlodipine maleate in the diet for up to two years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 mg amlodipine/kg/day, showed no evidence of a carcinogenic effect of the drug. For the mouse, the highest dose was, on mg/m2 basis, similar to the maximum recommended human dose [MRHD] of 10 mg amlodipine/day. For the rat, the highest dose was, on a mg/m2 basis, about two and a half times the MRHD. (Calculations based on a 60 kg patient.)

Mutagenicity studies conducted with amlodipine maleate revealed no drug-related effects at either the gene or chromosome level.

There was no effect on the fertility of rats treated orally with amlodipine maleate (males for 64 days and females for 14 days prior to mating) at doses of up to 10 mg amlodipine/kg/day (about 10 times the MRHD of 10 mg/day on a mg/m2 basis).

  Developmental Toxicity

Telmisartan
No teratogenic effects were observed when telmisartan was administered to pregnant rats at oral doses of up to 50 mg/kg/day and to pregnant rabbits at oral doses up to 45 mg/kg/day. In rabbits, embryolethality associated with maternal toxicity (reduced body weight gain and food consumption) was observed at 45 mg/kg/day [about 12 times the maximum recommended human dose (MRHD) of 80 mg on a mg/m2 basis]. In rats, maternally toxic (reduction in body weight gain and food consumption) telmisartan doses of 15 mg/kg/day (about 1.9 times the MRHD on a mg/m2 basis), administered during late gestation and lactation, were observed to produce adverse effects in neonates, including reduced viability, low birth weight, delayed maturation, and decreased weight gain. Telmisartan has been shown to be present in rat fetuses during late gestation and in rat milk. The no observed effect doses for developmental toxicity in rats and rabbits, 5 and 15 mg/kg/day, respectively, are about 0.64 and 3.7 times, on a mg/m2 basis, the maximum recommended human dose of telmisartan (80 mg/day).

Amlodipine
No evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats and rabbits were treated orally with amlodipine maleate at doses of up to 10 mg amlodipine/kg/day (respectively, about 10 and 20 times the maximum recommended human dose [MRHD] of 10 mg amlodipine on a mg/m2 basis) during their respective periods of major organogenesis. (Calculations based on a patient weight of 60 kg.) However, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold) for rats receiving amlodipine maleate at a dose equivalent to 10 mg amlodipine/kg/day for 14 days before mating and throughout mating and gestation. Amlodipine maleate has been shown to prolong both the gestation period and the duration of labor in rats at this dose.