Binosto

The most common side effects of Binosto are:

• Stomach area (abdominal) pain
• Heartburn
• Constipation
• Diarrhea
• Upset stomach
• Pain in your bones, joints, or muscles
• Nausea

You may get allergic reactions, such as hives or, in rare cases, swelling of your face, lips, tongue, or throat.

Tell your doctor if you have any side effect that bothers you or that does not go away.

Binosto may cause serious side effects. See "Drug Precautions."

These are not all the possible side effects of Binosto. For more information, ask your doctor or pharmacist.

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take:

• antacids
• calcium supplements
• aspirin
• nonsteroidal anti-inflammatory drugs (NSAIDS) like ibuprofen (Advil, Motrin) or naproxen (Aleve)

This is not a complete list of Binosto drug interactions. Ask your doctor or pharmacist for more information.

Alendronate is in the group of medicines called bisphosphonates (bis FOS fo nayts). It alters the cycle of bone formation and breakdown in the body. Alendronate slows bone loss while increasing bone mass, which may prevent bone fractures.

Alendronate is used in men and women to treat or prevent osteoporosis that is caused by menopause or by taking steroids. Alendronate is also used to increase bone mass in men who have osteoporosis, and to treat Paget's disease of bone in men and women.

Alendronate may also be used for purposes not listed in this medication guide.

If you take alendronate once daily: If you forget to take this medicine first thing in the morning, do not take it later in the day. Wait until the following morning to take the medicine and skip the missed dose. Do not take two (2) tablets in one day.

If you take alendronate once a week: If you forget to take alendronate on your scheduled day, take it first thing in the morning on the day after you remember the missed dose. Then return to your regular weekly schedule on your chosen dose day. Do not take two (2) tablets in one day.

Get emergency medical help if you have signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Stop using alendronate and call your doctor at once if you have:

• chest pain, new or worsening heartburn;

• difficulty or pain when swallowing;

• pain or burning under the ribs or in the back;

• severe heartburn, burning pain in your upper stomach, or coughing up blood;

• new or worsening heartburn;

• severe joint, bone, or muscle pain, new or unusual pain in your thigh or hip;

• fever, body aches, flu symptoms; or

• jaw pain, numbness, or swelling.

• new or unusual pain in your thigh or hip;

Common side effects may include:

• heartburn, upset stomach;

• stomach pain, nausea;

• diarrhea, constipation; or

• bone pain, muscle or joint pain.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• This medicine comes with an extra patient fact sheet called a Medication Guide. Read it with care. Read it again each time Binosto (alendronate effervescent tablets) is refilled. If you have any questions about this medicine, please talk with the doctor, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take Binosto or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to Binosto. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Review Date: October 4, 2017

Significant lethality after single oral doses was seen in female rats and mice at 552 mg/kg (3256 mg/m2) and 966 mg/kg (2898 mg/m2), respectively. In males, these values were slightly higher, 626 and 1280 mg/kg, respectively. There was no lethality in dogs at oral doses up to 200 mg/kg (4000 mg/m2).

No specific information is available on the treatment of overdosage with Binosto. Hypocalcemia, hypophosphatemia, and upper gastrointestinal adverse events, such as upset stomach, heartburn, esophagitis, gastritis, or ulcer, may result from oral overdosage. Milk or antacids should be given to bind alendronate. Due to the risk of esophageal irritation, vomiting should not be induced and the patient should remain fully upright.

Dialysis would not be beneficial.

Mechanism of Action

Animal studies have indicated the following mode of action. At the cellular level, alendronate shows preferential localization to sites of bone resorption, specifically under osteoclasts. The osteoclasts adhere normally to the bone surface but lack the ruffled border that is indicative of active resorption. Alendronate does not interfere with osteoclast recruitment or attachment, but it does inhibit osteoclast activity. Studies in mice on the localization of radioactive [3H]alendronate in bone showed about 10-fold higher uptake on osteoclast surfaces than on osteoblast surfaces. Bones examined 6 and 49 days after [3H]alendronate administration in rats and mice, respectively, showed that normal bone was formed on top of the alendronate, which was incorporated inside the matrix. While incorporated in bone matrix, alendronate is not pharmacologically active. Thus, alendronate must be continuously administered to suppress osteoclasts on newly formed resorption surfaces. Histomorphometry in baboons and rats showed that alendronate treatment reduces bone turnover (i.e., the number of sites at which bone is remodeled). In addition, bone formation exceeds bone resorption at these remodeling sites, leading to progressive gains in bone mass.

Pharmacodynamics

Alendronate is a bisphosphonate that binds to bone hydroxyapatite and specifically inhibits the activity of osteoclasts, the bone-resorbing cells. Alendronate reduces bone resorption with no direct effect on bone formation, although the latter process is ultimately reduced because bone resorption and formation are coupled during bone turnover.

Osteoporosis is characterized by low bone mass that leads to an increased risk of fracture. The diagnosis can be confirmed by the finding of low bone mass, evidence of fracture on x-ray, a history of osteoporotic fracture, or height loss or kyphosis, indicative of vertebral (spinal) fracture. Osteoporosis occurs in both males and females but is most common among women following the menopause, when bone turnover increases and the rate of bone resorption exceeds that of bone formation. These changes result in progressive bone loss and lead to osteoporosis in a significant proportion of women over age 50. Fractures, usually of the spine, hip, and wrist, are the common consequences. From age 50 to age 90, the risk of hip fracture in white women increases 50-fold and the risk of vertebral fracture 15- to 30-fold. It is estimated that approximately 40% of 50-year-old women will sustain one or more osteoporosis-related fractures of the spine, hip, or wrist during their remaining lifetimes. Hip fractures, in particular, are associated with substantial morbidity, disability, and mortality.

Daily oral doses of alendronate sodium (5, 20, and 40 mg for six weeks) in postmenopausal women produced biochemical changes indicative of dose-dependent inhibition of bone resorption, including decreases in urinary calcium and urinary markers of bone collagen degradation (such as deoxypyridinoline and cross-linked N-telopeptides of type I collagen). These biochemical changes tended to return toward baseline values as early as 3 weeks following the discontinuation of therapy with alendronate and did not differ from placebo after 7 months.

Long-term treatment of osteoporosis with alendronate sodium 10 mg/day (for up to five years) reduced urinary excretion of markers of bone resorption, deoxypyridinoline and cross-linked N-telopeptides of type l collagen, by approximately 50% and 70%, respectively, to reach levels similar to those seen in healthy premenopausal women. Similar decreases were seen in patients in osteoporosis prevention studies who received alendronate sodium 5 mg/day. The decrease in the rate of bone resorption indicated by these markers was evident as early as 1 month and at 3 to 6 months reached a plateau that was maintained for the entire duration of treatment with alendronate sodium. In osteoporosis treatment studies alendronate sodium 10 mg/day decreased the markers of bone formation, osteocalcin and bone specific alkaline phosphatase by approximately 50%, and total serum alkaline phosphatase by approximately 25 to 30% to reach a plateau after 6 to 12 months. In osteoporosis prevention studies alendronate sodium 5 mg/day decreased osteocalcin and total serum alkaline phosphatase by approximately 40% and 15%, respectively. Similar reductions in the rate of bone turnover were observed in postmenopausal women during one-year studies with once weekly alendronate sodium 70 mg for the treatment of osteoporosis and once weekly alendronate sodium 35 mg for the prevention of osteoporosis. These data indicate that the rate of bone turnover reached a new steady state, despite the progressive increase in the total amount of alendronate deposited within bone.

As a result of inhibition of bone resorption, asymptomatic reductions in serum calcium and phosphate concentrations were also observed following treatment with alendronate sodium. In the long-term studies, reductions from baseline in serum calcium (approximately 2%) and phosphate (approximately 4 to 6%) were evident the first month after the initiation of alendronate sodium 10 mg. No further decreases in serum calcium were observed for the five-year duration of treatment; however, serum phosphate returned toward prestudy levels during years three through five. Similar reductions were observed with alendronate sodium 5 mg/day. In one-year studies with once weekly alendronate sodium 35 and 70 mg, similar reductions were observed at 6 and 12 months. The reduction in serum phosphate may reflect not only the positive bone mineral balance due to alendronate sodium but also a decrease in renal phosphate reabsorption.

Treatment of men with osteoporosis with alendronate sodium 10 mg/day for two years reduced urinary excretion of cross-linked N-telopeptides of type I collagen by approximately 60% and bone-specific alkaline phosphatase by approximately 40%. Similar reductions were observed in a one-year study in men with osteoporosis receiving once weekly alendronate sodium 70 mg.

Pharmacokinetics

Relative to an intravenous (IV) reference dose, the mean oral bioavailability of alendronate in women was 0.64% for doses ranging from 5 to 70 mg when administered after an overnight fast and two hours before a standardized breakfast. Oral bioavailability of the 10 mg tablet in men (0.59%) was similar to that in women when administered after an overnight fast and 2 hours before breakfast.

Binosto 70 mg effervescent tablet and alendronate sodium 70 mg tablet are bioequivalent.

A study evaluating the effect of food on the bioavailability of Binosto was performed in 119 healthy women. Bioavailability was decreased (by approximately 50%) when 70 mg alendronate sodium was administered 15 minutes before a standardized breakfast, when compared to dosing 4 hours before eating.

In studies of treatment and prevention of osteoporosis, alendronate was effective when administered at least 30 minutes before breakfast.

Bioavailability was negligible whether alendronate sodium was administered with or up to 2 hours after a standardized breakfast. Concomitant administration of alendronate with coffee or orange juice reduced bioavailability by approximately 60%.

Preclinical studies (in male rats) show that alendronate sodium transiently distributes to soft tissues following 1 mg/kg IV administration but is then rapidly redistributed to bone or excreted in the urine. The mean steady-state volume of distribution, exclusive of bone, is at least 28 L in humans. Concentrations of drug in plasma following therapeutic oral doses are too low (less than 5 ng/mL) for analytical detection. Protein binding in human plasma is approximately 78%.

There is no evidence that alendronate sodium is metabolized in animals or humans.

Following a single IV dose of [14C]alendronate, approximately 50% of the radioactivity was excreted in the urine within 72 hours and little or no radioactivity was recovered in the feces. Following a single 10 mg IV dose, the renal clearance of alendronate was 71 mL/min (64, 78; 90% confidence interval [CI]), and systemic clearance did not exceed 200 mL/min. Plasma concentrations fell by more than 95% within 6 hours following IV administration. The terminal half-life in humans is estimated to exceed 10 years, probably reflecting release of alendronate from the skeleton. Based on the above, it is estimated that after 10 years of oral treatment with alendronate sodium (10 mg daily) the amount of alendronate released daily from the skeleton is approximately 25% of that absorbed from the gastrointestinal tract.

Gender: Bioavailability and the fraction of an intravenous dose excreted in urine were similar in men and women.

Geriatric: Bioavailability and disposition (urinary excretion) were similar in elderly and younger patients. No dosage adjustment is necessary in elderly patients.

Race: Pharmacokinetic differences due to race have not been studied.

Renal Impairment: Preclinical studies show that, in rats with kidney failure, increasing amounts of drug are present in plasma, kidney, spleen, and tibia. In healthy controls, drug that is not deposited in bone is rapidly excreted in the urine. No evidence of saturation of bone uptake was found after 3 weeks dosing with cumulative intravenous doses of 35 mg/kg in young male rats. Although no formal renal impairment pharmacokinetic study has been conducted in patients, it is likely that, as in animals, elimination of alendronate via the kidney will be reduced in patients with impaired renal function. Therefore, somewhat greater accumulation of alendronate in bone might be expected in patients with impaired renal function.

No dosage adjustment is necessary for patients with creatinine clearance 35 to 60 mL/min. Binosto is not recommended for patients with creatinine clearance less than 35 mL/min due to lack of experience with alendronate in renal failure.

Hepatic Impairment: As there is evidence that alendronate is not metabolized or exreted in the bile, no studies were conducted in patients with hepatic impairment. No dosage adjustment is necessary.

Ranitidine: Intravenous ranitidine was shown to double the bioavailability of oral alendronate. The clinical significance of this increased bioavailability and whether similar increases will occur in patients given oral H2-antagonists is unknown.

Prednisone: In healthy subjects, oral prednisone (20 mg three times daily for five days) did not produce a clinically meaningful change in the oral bioavailability of alendronate (a mean increase ranging from 20 to 44%).

Calcium and Multivalent Cations: Products containing calcium and other multivalent cations are likely to interfere with absorption of alendronate.

Levothyroxine: The geometric mean AUC(0-∞) and Cmax of alendronate decreased by 7% (point estimate: 0.93; 90% CI: 0.79-1.08) and 9% (point estimate: 0.91; 90% CI: 0.77-1.08), respectively, when a single dose of Binosto (70 mg alendronate) and 600 mcg levothyroxine were given concomitantly to 29 healthy male and female subjects.

You should not take Binosto if you have low levels of calcium in your blood (hypocalcemia), or a problem with the movement of muscles in your esophagus.

Do not take an Binosto tablet if you cannot sit upright or stand for at least 30 minutes. Alendronate can cause serious problems in the stomach or esophagus (the tube that connects your mouth and stomach). You will need to stay upright for at least 30 minutes after taking this medication.

You should not take Binosto if you are allergic to alendronate, or if you have low levels of calcium in your blood (hypocalcemia), or a problem with the movement of muscles in your esophagus.

Do not take Binosto if you cannot sit upright or stand for at least 30 minutes. Alendronate can cause serious problems in the stomach or esophagus (the tube that connects your mouth and stomach). You will need to stay upright for at least 30 minutes after taking this medication.

To make sure Binosto is safe for you, tell your doctor if you have:

• trouble swallowing;

• a vitamin D deficiency;

• a dental problem;

• kidney disease; or

• an ulcer or other problem in your stomach or esophagus.

In rare cases, this medicine may cause bone loss (osteonecrosis) in the jaw. Symptoms include jaw pain or numbness, red or swollen gums, loose teeth, or slow healing after dental work. The longer you use Binosto, the more likely you are to develop this condition.

Osteonecrosis of the jaw may be more likely if you have cancer or received chemotherapy, radiation, or steroids. Other risk factors include blood clotting disorders, anemia (low red blood cells), and a pre existing dental problem.

Talk with your doctor about the risks and benefits of using this medication.

It is not known whether Binosto will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication.

It is not known whether alendronate passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

Applies to alendronate: oral solution, oral tablet, oral tablet effervescent

Along with its needed effects, alendronate (the active ingredient contained in Binosto) 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 while taking alendronate:

• Abdominal or stomach pain

• Difficulty with swallowing
• heartburn
• irritation or pain of the esophagus
• muscle pain

• Skin rash

• Abdominal or stomach cramps
• blistering, peeling, or loosening of the skin
• bloating or swelling of the face, arms, hands, lower legs, or feet
• bone, joint, or muscle pain, severe and occasionally incapacitating
• chest pain
• chills
• confusion
• convulsions
• cough
• diarrhea
• difficulty with breathing
• difficulty with moving
• heartburn
• heavy jaw feeling
• hives or welts
• irregular heartbeats
• itching
• joint pain
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• loosening of a tooth
• muscle aching or cramping
• muscle cramps in the hands, arms, feet, legs, or face
• numbness and tingling around the mouth, fingertips, or feet
• pain or burning in the throat
• pain, swelling, or numbness in the mouth or jaw
• rapid weight gain
• red skin lesions, often with a purple center
• red, irritated eyes
• redness of the skin
• shortness of breath
• sore throat
• sores, ulcers, or white spots on the lips or tongue or inside the mouth
• swollen joints
• tingling of the hands or feet
• tremor
• unusual tiredness or weakness
• unusual weight gain or loss
• vomiting

Some side effects of alendronate 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:

• Constipation
• diarrhea
• full or bloated feeling
• gas
• headache
• nausea

• Blurred vision or other change in vision
• dizziness or lightheadedness
• eye pain
• feeling of constant movement of self or surroundings
• general feeling of discomfort or illness
• hair loss or thinning of the hair
• sensation of spinning
• sensitivity of the eye to light
• tearing