These Highlights Do Not Include All The Information Needed To Use Binosto®

Treatment of Osteoporosis in Postmenopausal Women

Store at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F), [See USP Controlled Room Temperature.] Protect from moisture. Store tablets in original blister package until use.

In clinical studies, the incidence of upper gastrointestinal adverse events was increased in patients receiving concomitant therapy with daily doses of alendronate sodium greater than 10 mg and aspirin-containing products.

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.

BINOSTO (alendronate sodium) is a bisphosphonate that acts as a specific inhibitor of osteoclast-mediated bone resorption. Bisphosphonates are synthetic analogs of pyrophosphate that bind to the hydroxyapatite found in bone.

Alendronate sodium is chemically described as (4 amino-1-hydroxybutylidene) bisphosphonic acid, monosodium salt, trihydrate. The molecular formula of alendronate sodium is C₄H₁₂NNaO₇P₂ ∙ 3H₂O and its molecular weight is 325.12. The structural formula of alendronate sodium is

Alendronate sodium is a white or almost white crystalline powder that is soluble in water, very slightly soluble in methanol, and practically insoluble in methylene chloride.

BINOSTO for oral administration is an effervescent tablet formulation that must be dissolved in water before use. Each individual tablet contains 91.37 mg of alendronate sodium, which is equivalent to 70 mg of free alendronic acid. Each tablet also contains the following inactive ingredients: monosodium citrate anhydrous, citric acid anhydrous, sodium hydrogen carbonate, and sodium carbonate anhydrous as buffering agents, strawberry flavor, acesulfame potassium, and sucralose.

70 mg of BINOSTO effervescent tablet contains 603 mg of sodium and 17 mg of phosphorus.

Once the effervescent tablet is dissolved in water, the alendronate sodium is present in a citrate-buffered solution of pH 4.8 to 5.4.

The bioavailability of alendronate was slightly decreased when BINOSTO and levothyroxine were co-administered to healthy subjects [see Clinical Pharmacology (12.3)].

BINOSTO is not indicated for use in pediatric patients.

The safety and efficacy of alendronate sodium were examined in a randomized, double-blind, placebo-controlled two-year study of 139 pediatric patients, aged 4-18 years, with severe osteogenesis imperfecta (OI). One-hundred-and-nine patients were randomized to 5 mg alendronate sodium daily (weight less than 40 kg) or 10 mg alendronate sodium daily (weight greater than or equal to 40 kg) and 30 patients to placebo. The mean baseline lumbar spine BMD Z-score of the patients was -4.5. The mean change in lumbar spine BMD Z-score from baseline to Month 24 was 1.3 in the alendronate-treated patients and 0.1 in the placebo- treated patients. Treatment with alendronate sodium did not reduce the risk of fracture. Sixteen percent of the alendronate-treated patients who sustained a radiologically-confirmed fracture by Month 12 of the study had delayed fracture healing (callus remodeling) or fracture non-union when assessed radiographically at Month 24 compared with 9% of the placebo-treated patients. In alendronate-treated patients, bone histomorphometry data obtained at Month 24 demonstrated decreased bone turnover and delayed mineralization time; however, there were no mineralization defects. There were no statistically significant differences between the alendronate sodium and placebo groups in reduction of bone pain. The oral bioavailability in children was similar to that observed in adults.

The overall safety profile of alendronate sodium in osteogenesis imperfecta patients treated for up to 24 months was generally similar to that of adults with osteoporosis treated with alendronate sodium. However, there was an increased occurrence of vomiting in osteogenesis imperfecta patients treated with alendronate sodium compared to placebo. During the 24-month treatment period, vomiting was observed in 32 of 109 (29.4%) patients treated with alendronate sodium and 3 of 30 (10%) patients treated with placebo.

In a pharmacokinetic study, 6 of 24 pediatric osteogenesis imperfecta patients who received a single oral dose of alendronate sodium 35 or 70 mg developed fever, flu-like symptoms, and/or mild lymphocytopenia within 24 to 48 hours after administration. These events, lasting no more than 2 to 3 days and responding to acetaminophen, are consistent with an acute-phase response that has been reported in patients receiving bisphosphonates, including alendronate sodium. [See Adverse Reactions (6.2).]

Of the patients receiving alendronate sodium in the Fracture Intervention Trial (FIT), 71% (n=2302) were greater than or equal to 65 years of age and 17% (n=550) were greater than or equal to 75 years of age. Of the patients receiving alendronate sodium in the United States and Multinational osteoporosis treatment studies in women and osteoporosis studies in men, [see Clinical Studies (14.1), (14.2)], 45% and 54%, respectively, were 65 years of age or over. No overall differences in efficacy or safety were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

BINOSTO is contraindicated in patients with the following conditions:

• Abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia [see Warnings and Precautions (5.1)]
• Inability to stand or sit upright for at least 30 minutes [see Dosage and Administration (2.3); Warnings and Precautions (5.1)]

Do not administer BINOSTO to patients at increased risk of aspiration

• Hypocalcemia [see Warnings and Precautions (5.2)]
• Hypersensitivity to any component of this product. Hypersensitivity reactions including urticaria and angioedema have been reported [see Adverse Reactions (6.2)].

The following clinically significant adverse drug reactions are described elsewhere in the labeling:

• Upper Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.1)]
• Mineral Metabolism [see Warnings and Precautions (5.2)]
• Musculoskeletal Pain [see Warnings and Precautions (5.3)]
• Osteonecrosis of the Jaw [see Warnings and Precautions (5.4)]
• Atypical Fractures Including Femoral Fractures [see Warnings and Precautions (5.5)]
• Renal Impairment [see Warnings and Precautions (5.6)]
• Patients sensitive to High Sodium Intake [see Warnings and Precautions (5.7)]

• Calcium supplements, antacids or oral medications containing multivalent cations interfere with absorption of alendronate. (7.1)
• Use caution when co-prescribing aspirin/nonsteroidal anti- inflammatory drugs that may worsen gastrointestinal irritation. (7.2, 7.3)

BINOSTO is not recommended for patients with creatinine clearance <35 mL/min.

BINOSTO is not recommended for patients with creatinine clearance less than 35 mL/min. No dosage adjustment is necessary in patients with creatinine clearance values between 35-60 mL/min [see Clinical Pharmacology (12.3)].

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.

Hypocalcemia must be corrected before initiating therapy with BINOSTO [see Contraindications (4)]. Other disorders affecting mineral metabolism (such as vitamin D deficiency) should also be effectively treated. In patients with these conditions, serum calcium and symptoms of hypocalcemia should be monitored during therapy with BINOSTO.

Presumably due to the effects of BINOSTO on increasing bone mineral, small, asymptomatic decreases in serum calcium and phosphate may occur. Patients should receive adequate calcium and vitamin D intake.

As there is evidence that alendronate is not metabolized or excreted in the bile, no studies were conducted in patients with hepatic impairment. No dosage adjustment is necessary [see Clinical Pharmacology (12.3)].

BINOSTO is a bisphosphonate indicated for:

• Treatment of osteoporosis in postmenopausal women (1.1)
• Treatment to increase bone mass in men with osteoporosis (1.2)

Limitation of use: Optimal duration of use has not been determined. For patients at low-risk for fracture, consider drug discontinuation after 3 to 5 years of use (1.3)

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.

Instruct patients that it is necessary to follow all dosing instructions for BINOSTO:

• BINOSTO should only be taken upon arising for the day and must be taken at least 30 minutes before the first food, beverage, or medication of the day. Instruct patients not to attempt to swallow, chew, or suck on the tablet because of a potential for oropharyngeal ulceration.
• Instruct patients to dissolve the effervescent tablet in 4 ounces room temperature plain water only (not mineral water or flavored water).
• Instruct patients to wait at least 5 minutes after the effervescence stops and then stir the solution for approximately 10 seconds and then consume the contents.
• Instruct patients to avoid lying down for at least 30 minutes after taking BINOSTO and until after their first food of the day.
• Instruct patients not to take BINOSTO at bedtime or before arising for the day.
• Instruct patients that waiting less than 30 minutes, or taking BINOSTO with food, beverages (other than plain water) or other medications will lessen the effect of BINOSTO by decreasing its absorption into the body [see Drug Interactions (7.1)]. Even dosing with orange juice or coffee has been shown to markedly reduce the absorption of BINOSTO [see Clinical Pharmacology (12.3)].
• Inform patients that failure to follow these instructions may increase their risk of esophageal problems. [see Warnings and Precautions (5.1)].

Instruct patients that if they develop symptoms of esophageal disease (such as difficulty or pain upon swallowing, retrosternal pain or new or worsening heartburn) they should stop taking BINOSTO and consult their physician. [see Warnings and Precautions (5.1)].

Instruct patients that if they miss a dose of once weekly BINOSTO, they should take one dose on the morning after they remember. They should not take 2 doses on the same day but should return to taking one dose once a week, as originally scheduled on their chosen day.

In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates that are approved for the treatment of osteoporosis [see Adverse Reactions (6.2)]. This category of drugs includes BINOSTO. Most of the patients were postmenopausal women. The time to onset of symptoms varied from one day to several months after starting the drug. Discontinue use if severe symptoms develop. Most patients had relief of symptoms after stopping. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate.

In placebo-controlled clinical studies of alendronate sodium, the percentages of patients with these symptoms were similar in the alendronate sodium and placebo groups.

• Upper Gastrointestinal Adverse Reactions can occur. Instruct patients to follow dosing instructions. Discontinue if new or worsening symptoms occur. (5.1)
• Hypocalcemia can worsen and must be corrected prior to use. (5.2)
• Severe Bone, Joint, Muscle Pain may occur. Discontinue use if severe symptoms develop. (5.3)
• Osteonecrosis of the Jaw has been reported. (5.4)
• Atypical Fractures Including Femoral Fractures have been reported. Patients with new thigh or groin pain should be evaluated to rule out a femoral fracture. Risk/benefit of continuing bisphosphonate therapy should be re-evaluated in these patients and interruption of bisphosphonate therapy should be considered. (5.5)
• Sodium Content: Each tablet contains 603 mg sodium, equivalent to 1532 mg NaCl. Use caution in patients on sodium restriction. (5.7)

• 70 mg BINOSTO effervescent tablet once weekly. (2.1, 2.2)
• Instruct patients to: (2.3)
  • Dissolve one tablet of BINOSTO in approximately half a glass of plain room temperature water (4 oz). Wait at least 5 minutes after the effervescence stops, stir the solution for approximately 10 seconds and consume contents.
  • Swallow solution at least 30 minutes before the first food, beverage, or medication of the day.
  • Avoid lying down for at least 30 minutes after taking BINOSTO and until after the first food of the day.

BINOSTO effervescent tablets are round, flat-faced, white to off-white tablets, 25 mm in diameter, with beveled edges, with "M" debossed on one side, containing 91.37 mg of alendronate sodium, which is equivalent to 70 mg of free alendronic acid. After dissolution the solution has a pH of 4.8-5.4.

Osteonecrosis of the jaw (ONJ), which can occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing, and has been reported in patients taking bisphosphonates, including alendronate sodium. Known risk factors for osteonecrosis of the jaw include invasive dental procedures (e.g., tooth extraction, dental implants, boney surgery), diagnosis of cancer, concomitant therapies (e.g., chemotherapy, corticosteroids, angiogenesis inhibitors), poor oral hygiene, and co-morbid disorders (e.g., periodontal and/or other pre-existing dental disease, anemia, coagulopathy, infection, ill-fitting dentures). The risk of ONJ may increase with duration of exposure to bisphosphonates.

For patients requiring invasive dental procedures, discontinuation of bisphosphonate treatment may reduce the risk for ONJ. Clinical judgment of the treating physician and/or oral surgeon should guide the management plan of each patient based on individual benefit/risk assessment.

Patients who develop osteonecrosis of the jaw while on bisphosphonate therapy should receive care by an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Discontinuation of bisphosphonate therapy should be considered based on individual benefit/risk assessment.

The following adverse reactions have been identified during post-approval use of alendronate sodium or bisphosphonate products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole: hypersensitivity reactions including urticaria and angioedema. Transient symptoms of myalgia, malaise, asthenia and fever have been reported with alendronate, typically in association with initiation of treatment. Symptomatic hypocalcemia has occurred, generally in association with predisposing conditions. Peripheral edema.

Gastrointestinal: esophagitis, esophageal erosions, esophageal ulcers, esophageal stricture or perforation, and oropharyngeal ulceration. Gastric or duodenal ulcers, some severe and with complications have also been reported [see Dosage and Administration (2.3); Warnings and Precautions (5.1)].

Dental: Localized osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection with delayed healing, has been reported [see Warnings and Precautions (5.4)].

Musculoskeletal: bone, joint, and/or muscle pain, occasionally severe and incapacitating [see Warnings and Precautions (5.3)]; joint swelling; low-energy femoral shaft and subtrochanteric fractures, and atypical fractures of other bones [see Warnings and Precautions (5.5].

Nervous system: dizziness and vertigo.

Pulmonary: acute asthma exacerbations

Skin: rash (occasionally with photosensitivity), pruritus, alopecia, severe skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis.

Special Senses: uveitis, scleritis or episcleritis. Cholesteatoma of the external auditory canal (focal osteonecrosis).

• Pregnancy: Discontinue when pregnancy is recognized. (8.1)
• BINOSTO is not indicated for use in pediatric patients. (8.4)
• BINOSTO is not recommended in patients with renal impairment (creatinine clearance less than 35 mL/min). (5.6, 8.6)

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The safety of BINOSTO (alendronate sodium) effervescent tablet 70 mg is based on clinical trial data of alendronate sodium 10 mg daily and alendronate sodium 70 mg weekly.

The optimal duration of use has not been determined. The safety and effectiveness of BINOSTO for the treatment of osteoporosis are based on clinical data of four years duration. All patients on bisphosphonate therapy should have the need for continued therapy re-evaluated on a periodic basis. Patients at low-risk for fracture should be considered for drug discontinuation after 3 to 5 years of use. Patients who discontinue therapy should have their risk for fracture re-evaluated periodically.

Co-administration of BINOSTO and calcium, antacids, or oral medications containing multivalent cations will interfere with absorption of BINOSTO. Therefore, instruct patients to wait at least one-half hour after taking BINOSTO before taking any other oral medications.

See FDA-approved patient labeling (Medication Guide).

Instruct patients to read the Medication Guide before starting therapy with BINOSTO and to reread it each time the prescription is renewed.

Inform patients who are prescribed sodium restricted diets that BINOSTO contains 603 mg of sodium which is equivalent to approximately 1532 mg NaCl per tablet.

BINOSTO effervescent tablets are round, flat faced, white to off-white tablets with beveled edges and "M" debossed on one side. BINOSTO effervescent tablets, 70 mg are provided in blisters made of aluminum foil composite, as follows:

NDC 70539-400-04 carton containing 4 units of use blisters

Instruct patients to do the following to assure adequate drug absorption and to decrease the risk of esophageal adverse reactions:

• Take BINOSTO upon arising for the day and at least 30 minutes before the first food, beverage, or medication of the day.
• Patients should not swallow the undissolved effervescent tablet, should not chew the effervescent tablet or allow the effervescent tablet to dissolve in their mouths because of the risk for oropharyngeal irritation [see Warnings and Precautions (5.1)].
• Dissolve the effervescent tablet in 4 ounces room temperature plain water only (not mineral water or flavored water).
• Wait at least 5 minutes after the effervescence stops and then stir the buffered solution for approximately 10 seconds and ingest.
• Avoid lying down for at least 30 minutes after taking BINOSTO and until after their first food of the day.
• Do not take BINOSTO at bedtime or before arising for the day.
  
  Failure to follow these instructions may increase the risk of esophageal adverse reactions [see Warnings and Precautions (5.1)].

The relative inhibitory activities on bone resorption and mineralization of alendronate and etidronate were compared in the Schenk assay, which is based on histological examination of the epiphyses of growing rats. In this assay, the lowest dose of alendronate that interfered with bone mineralization (leading to osteomalacia) was 6000-fold the antiresorptive dose. The corresponding ratio for etidronate was one to one. These data suggest that alendronate administered in therapeutic doses is highly unlikely to induce osteomalacia.

BINOSTO, like other bisphosphonates administered orally, may cause local irritation of the upper gastrointestinal mucosa. Because of these possible irritant effects and a potential for worsening of the underlying disease, caution should be used when BINOSTO is given to patients with active upper gastrointestinal problems (such as known Barrett's esophagus, dysphagia, other esophageal diseases, gastritis, duodenitis, or ulcers).

Esophageal adverse experiences, such as esophagitis, esophageal ulcers and esophageal erosions, occasionally with bleeding and rarely followed by esophageal stricture or perforation, have been reported in patients receiving treatment with oral bisphosphonates including alendronate sodium. In some cases these have been severe and required hospitalization. Physicians should therefore be alert to any signs or symptoms signaling a possible esophageal reaction and patients should be instructed to discontinue BINOSTO and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn.

The risk of severe esophageal adverse experiences appears to be greater in patients who lie down after taking oral bisphosphonates including alendronate sodium, and/or who continue to take oral bisphosphonates including alendronate sodium after developing symptoms suggestive of esophageal irritation. Therefore, it is very important that the full dosing instructions are provided to, and understood by, the patient [see Dosage and Administration (2.3)]. In patients who cannot comply with dosing instructions due to mental disability, therapy with BINOSTO should be used under appropriate supervision.

There have been post-marketing reports of gastric and duodenal ulcers with oral bisphosphonate use, some severe and with complications, although no increased risk was observed in controlled clinical trials [see Adverse Reactions (6.2)].

Each BINOSTO effervescent tablet contains 603 mg of sodium, equivalent to approximately 1532 mg of salt (NaCl). Use caution in patients who must restrict their sodium intake, including some patients with a history of heart failure, hypertension, or other cardiovascular diseases [see Patient Counseling Information (17.3)].

Fold and tear at

notch or cut

NDC 70539-400-00

Binosto^®

(alendronate sodium) effervescent

tablet for oral solution

70 mg

Rx only

This blister contains 1 complete week of treatment

2023-BIN-0001

Manufactured for:

Radius Health, Inc.

22 Boston Wharf Road, 7^th Floor

Boston, MA 02210 USA

If the once-weekly dose is missed, instruct patients to take one dose on the morning after they remember. They should not take 2 doses on the same day but should return to taking one dose once a week, as originally scheduled on their chosen day.

BINOSTO may be administered to patients taking NSAIDs. In a 3-year, controlled, clinical study (n=2027) during which a majority of patients received concomitant NSAIDs, the incidence of upper gastrointestinal adverse events was similar in patients taking alendronate sodium 5 or 10 mg/day compared to those taking placebo. However, since NSAID use is associated with gastrointestinal irritation, caution should be used during concomitant use with BINOSTO.

Atypical, low-energy, or low trauma fractures of the femoral shaft have been reported during treatment with bisphosphonates, including alendronate sodium, in patients with osteoporosis. Atypical femur and other fractures most commonly occur with minimal or no trauma to the affected area. These fractures occurred anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. Atypical fractures of other bones have also been reported. They may be bilateral. These fractures can also occur in osteoporotic patients who have not been treated with bisphosphonates. Concomitant treatment with glucocorticoids may also induce these fractures.

Prodromal pain in the affected area, usually presenting as dull, aching pain, weeks to months before a complete fracture occurs was reported by patients.

Any patient with a history of bisphosphonate exposure who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Bone pain in other locations should also be considered for evaluation of atypical fracture. Patients presenting with an atypical fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Risk/benefit of continuing bisphosphonate therapy should be re-evaluated in these patients and interruption of bisphosphonate therapy should be considered.

BINOSTO effervescent tablet 70 mg is indicated for the treatment of osteoporosis in postmenopausal women. For the treatment of osteoporosis, alendronate sodium increases bone mass and reduces the incidence of fractures, including those of the hip and spine (vertebral compression fractures). [See Clinical Studies (14.1).]

The recommended dosage is one 70 mg effervescent tablet once weekly.

BINOSTO (alendronate sodium) effervescent tablet 70 mg is bioequivalent to alendronate sodium tablet 70 mg. The fracture reduction efficacy and bone mineral density changes attributed to BINOSTO are based on clinical trial data of alendronate sodium 10 mg daily and alendronate sodium 70 mg weekly.

NDC 70539-400-04

Rx only

Binosto^®

(alendronate sodium) effervescent

tablet for oral solution

70 mg*

* Each effervescent tablet contains 91.37 mg

alendronate sodium (70 mg free acid equivalent)

4 Effervescent Tablets

ATTENTION PHARMACIST:

Each patient is required to

receive the medication guide.

Harderian gland (a retro-orbital gland not present in humans) adenomas were increased in high-dose female mice (p=0.003) in a 92-week oral carcinogenicity study at doses of alendronate of 1, 3, and 10 mg/kg/day (males) or 1, 2, and 5 mg/kg/day (females). These doses are equivalent to 0.12 to 1.2 times a maximum recommended daily dose of 40 mg, based on surface area, mg/m². The relevance of this finding to humans is unknown.

Parafollicular cell (thyroid) adenomas were increased in high-dose male rats (p=0.003) in a 2-year oral carcinogenicity study at doses of 1 and 3.75 mg/kg body weight. These doses are equivalent to 0.26 and 1 times a 40 mg human daily dose based on surface area, mg/m². The relevance of this finding to humans is unknown.

Alendronate sodium was not genotoxic in the in vitro microbial mutagenesis assay with and without metabolic activation, in an in vitro mammalian cell mutagenesis assay, in an in vitro alkaline elution assay in rat hepatocytes, and in an in vivo chromosomal aberration assay in mice. In an in vitro chromosomal aberration assay in Chinese hamster ovary cells, however, alendronate gave equivocal results.

Alendronate sodium had no effect on fertility (male or female) in rats at oral doses up to 5 mg/kg/day (1.3 times a 40 mg human daily dose based on surface area, mg/m²).

BINOSTO is indicated for treatment to increase bone mass in men with osteoporosis [see Clinical Studies (14.2)].

The recommended dosage is one 70 mg effervescent tablet once weekly.

The efficacy of alendronate sodium in men with hypogonadal or idiopathic osteoporosis was demonstrated in two clinical studies.

Instruct patients to take supplemental calcium and vitamin D if dietary intake is inadequate [see Warnings and Precautions (5.2)]. Patients at increased risk for vitamin D insufficiency (e.g., over the age of 70 years, nursing home-bound, or chronically ill) may need vitamin D supplementation. Patients with gastrointestinal malabsorption syndromes may require higher doses of vitamin D supplementation and measurement of 25-hydroxyvitamin D should be considered.

NDC 70539-400-94

Rx only

SAMPLE—NOT FOR SALE

Binosto^®

(alendronate sodium) effervescent

tablet for oral solution

70 mg*

* Each effervescent tablet contains 91.37 mg

alendronate sodium (70 mg free acid equivalent)

4 Effervescent Tablets

ATTENTION PHARMACIST:

Each patient is required to

receive the medication guide.

Instruct patients to take supplemental calcium and vitamin D, if daily dietary intake is inadequate. Weight-bearing exercise should be considered along with the modification of certain behavioral factors, such as cigarette smoking and/or excessive alcohol consumption, if these factors exist.

Treatment of Osteoporosis in Postmenopausal Women

Store at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F), [See USP Controlled Room Temperature.] Protect from moisture. Store tablets in original blister package until use.

In clinical studies, the incidence of upper gastrointestinal adverse events was increased in patients receiving concomitant therapy with daily doses of alendronate sodium greater than 10 mg and aspirin-containing products.

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.

BINOSTO (alendronate sodium) is a bisphosphonate that acts as a specific inhibitor of osteoclast-mediated bone resorption. Bisphosphonates are synthetic analogs of pyrophosphate that bind to the hydroxyapatite found in bone.

Alendronate sodium is chemically described as (4 amino-1-hydroxybutylidene) bisphosphonic acid, monosodium salt, trihydrate. The molecular formula of alendronate sodium is C₄H₁₂NNaO₇P₂ ∙ 3H₂O and its molecular weight is 325.12. The structural formula of alendronate sodium is

Alendronate sodium is a white or almost white crystalline powder that is soluble in water, very slightly soluble in methanol, and practically insoluble in methylene chloride.

BINOSTO for oral administration is an effervescent tablet formulation that must be dissolved in water before use. Each individual tablet contains 91.37 mg of alendronate sodium, which is equivalent to 70 mg of free alendronic acid. Each tablet also contains the following inactive ingredients: monosodium citrate anhydrous, citric acid anhydrous, sodium hydrogen carbonate, and sodium carbonate anhydrous as buffering agents, strawberry flavor, acesulfame potassium, and sucralose.

70 mg of BINOSTO effervescent tablet contains 603 mg of sodium and 17 mg of phosphorus.

Once the effervescent tablet is dissolved in water, the alendronate sodium is present in a citrate-buffered solution of pH 4.8 to 5.4.

The bioavailability of alendronate was slightly decreased when BINOSTO and levothyroxine were co-administered to healthy subjects [see Clinical Pharmacology (12.3)].

BINOSTO is not indicated for use in pediatric patients.

The safety and efficacy of alendronate sodium were examined in a randomized, double-blind, placebo-controlled two-year study of 139 pediatric patients, aged 4-18 years, with severe osteogenesis imperfecta (OI). One-hundred-and-nine patients were randomized to 5 mg alendronate sodium daily (weight less than 40 kg) or 10 mg alendronate sodium daily (weight greater than or equal to 40 kg) and 30 patients to placebo. The mean baseline lumbar spine BMD Z-score of the patients was -4.5. The mean change in lumbar spine BMD Z-score from baseline to Month 24 was 1.3 in the alendronate-treated patients and 0.1 in the placebo- treated patients. Treatment with alendronate sodium did not reduce the risk of fracture. Sixteen percent of the alendronate-treated patients who sustained a radiologically-confirmed fracture by Month 12 of the study had delayed fracture healing (callus remodeling) or fracture non-union when assessed radiographically at Month 24 compared with 9% of the placebo-treated patients. In alendronate-treated patients, bone histomorphometry data obtained at Month 24 demonstrated decreased bone turnover and delayed mineralization time; however, there were no mineralization defects. There were no statistically significant differences between the alendronate sodium and placebo groups in reduction of bone pain. The oral bioavailability in children was similar to that observed in adults.

The overall safety profile of alendronate sodium in osteogenesis imperfecta patients treated for up to 24 months was generally similar to that of adults with osteoporosis treated with alendronate sodium. However, there was an increased occurrence of vomiting in osteogenesis imperfecta patients treated with alendronate sodium compared to placebo. During the 24-month treatment period, vomiting was observed in 32 of 109 (29.4%) patients treated with alendronate sodium and 3 of 30 (10%) patients treated with placebo.

In a pharmacokinetic study, 6 of 24 pediatric osteogenesis imperfecta patients who received a single oral dose of alendronate sodium 35 or 70 mg developed fever, flu-like symptoms, and/or mild lymphocytopenia within 24 to 48 hours after administration. These events, lasting no more than 2 to 3 days and responding to acetaminophen, are consistent with an acute-phase response that has been reported in patients receiving bisphosphonates, including alendronate sodium. [See Adverse Reactions (6.2).]

Of the patients receiving alendronate sodium in the Fracture Intervention Trial (FIT), 71% (n=2302) were greater than or equal to 65 years of age and 17% (n=550) were greater than or equal to 75 years of age. Of the patients receiving alendronate sodium in the United States and Multinational osteoporosis treatment studies in women and osteoporosis studies in men, [see Clinical Studies (14.1), (14.2)], 45% and 54%, respectively, were 65 years of age or over. No overall differences in efficacy or safety were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

BINOSTO is contraindicated in patients with the following conditions:

• Abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia [see Warnings and Precautions (5.1)]
• Inability to stand or sit upright for at least 30 minutes [see Dosage and Administration (2.3); Warnings and Precautions (5.1)]

Do not administer BINOSTO to patients at increased risk of aspiration

• Hypocalcemia [see Warnings and Precautions (5.2)]
• Hypersensitivity to any component of this product. Hypersensitivity reactions including urticaria and angioedema have been reported [see Adverse Reactions (6.2)].

The following clinically significant adverse drug reactions are described elsewhere in the labeling:

• Upper Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.1)]
• Mineral Metabolism [see Warnings and Precautions (5.2)]
• Musculoskeletal Pain [see Warnings and Precautions (5.3)]
• Osteonecrosis of the Jaw [see Warnings and Precautions (5.4)]
• Atypical Fractures Including Femoral Fractures [see Warnings and Precautions (5.5)]
• Renal Impairment [see Warnings and Precautions (5.6)]
• Patients sensitive to High Sodium Intake [see Warnings and Precautions (5.7)]

• Calcium supplements, antacids or oral medications containing multivalent cations interfere with absorption of alendronate. (7.1)
• Use caution when co-prescribing aspirin/nonsteroidal anti- inflammatory drugs that may worsen gastrointestinal irritation. (7.2, 7.3)

BINOSTO is not recommended for patients with creatinine clearance <35 mL/min.

BINOSTO is not recommended for patients with creatinine clearance less than 35 mL/min. No dosage adjustment is necessary in patients with creatinine clearance values between 35-60 mL/min [see Clinical Pharmacology (12.3)].

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.

Hypocalcemia must be corrected before initiating therapy with BINOSTO [see Contraindications (4)]. Other disorders affecting mineral metabolism (such as vitamin D deficiency) should also be effectively treated. In patients with these conditions, serum calcium and symptoms of hypocalcemia should be monitored during therapy with BINOSTO.

Presumably due to the effects of BINOSTO on increasing bone mineral, small, asymptomatic decreases in serum calcium and phosphate may occur. Patients should receive adequate calcium and vitamin D intake.

As there is evidence that alendronate is not metabolized or excreted in the bile, no studies were conducted in patients with hepatic impairment. No dosage adjustment is necessary [see Clinical Pharmacology (12.3)].

BINOSTO is a bisphosphonate indicated for:

• Treatment of osteoporosis in postmenopausal women (1.1)
• Treatment to increase bone mass in men with osteoporosis (1.2)

Limitation of use: Optimal duration of use has not been determined. For patients at low-risk for fracture, consider drug discontinuation after 3 to 5 years of use (1.3)

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.

Instruct patients that it is necessary to follow all dosing instructions for BINOSTO:

• BINOSTO should only be taken upon arising for the day and must be taken at least 30 minutes before the first food, beverage, or medication of the day. Instruct patients not to attempt to swallow, chew, or suck on the tablet because of a potential for oropharyngeal ulceration.
• Instruct patients to dissolve the effervescent tablet in 4 ounces room temperature plain water only (not mineral water or flavored water).
• Instruct patients to wait at least 5 minutes after the effervescence stops and then stir the solution for approximately 10 seconds and then consume the contents.
• Instruct patients to avoid lying down for at least 30 minutes after taking BINOSTO and until after their first food of the day.
• Instruct patients not to take BINOSTO at bedtime or before arising for the day.
• Instruct patients that waiting less than 30 minutes, or taking BINOSTO with food, beverages (other than plain water) or other medications will lessen the effect of BINOSTO by decreasing its absorption into the body [see Drug Interactions (7.1)]. Even dosing with orange juice or coffee has been shown to markedly reduce the absorption of BINOSTO [see Clinical Pharmacology (12.3)].
• Inform patients that failure to follow these instructions may increase their risk of esophageal problems. [see Warnings and Precautions (5.1)].

Instruct patients that if they develop symptoms of esophageal disease (such as difficulty or pain upon swallowing, retrosternal pain or new or worsening heartburn) they should stop taking BINOSTO and consult their physician. [see Warnings and Precautions (5.1)].

Instruct patients that if they miss a dose of once weekly BINOSTO, they should take one dose on the morning after they remember. They should not take 2 doses on the same day but should return to taking one dose once a week, as originally scheduled on their chosen day.

In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates that are approved for the treatment of osteoporosis [see Adverse Reactions (6.2)]. This category of drugs includes BINOSTO. Most of the patients were postmenopausal women. The time to onset of symptoms varied from one day to several months after starting the drug. Discontinue use if severe symptoms develop. Most patients had relief of symptoms after stopping. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate.

In placebo-controlled clinical studies of alendronate sodium, the percentages of patients with these symptoms were similar in the alendronate sodium and placebo groups.

• Upper Gastrointestinal Adverse Reactions can occur. Instruct patients to follow dosing instructions. Discontinue if new or worsening symptoms occur. (5.1)
• Hypocalcemia can worsen and must be corrected prior to use. (5.2)
• Severe Bone, Joint, Muscle Pain may occur. Discontinue use if severe symptoms develop. (5.3)
• Osteonecrosis of the Jaw has been reported. (5.4)
• Atypical Fractures Including Femoral Fractures have been reported. Patients with new thigh or groin pain should be evaluated to rule out a femoral fracture. Risk/benefit of continuing bisphosphonate therapy should be re-evaluated in these patients and interruption of bisphosphonate therapy should be considered. (5.5)
• Sodium Content: Each tablet contains 603 mg sodium, equivalent to 1532 mg NaCl. Use caution in patients on sodium restriction. (5.7)

• 70 mg BINOSTO effervescent tablet once weekly. (2.1, 2.2)
• Instruct patients to: (2.3)
  • Dissolve one tablet of BINOSTO in approximately half a glass of plain room temperature water (4 oz). Wait at least 5 minutes after the effervescence stops, stir the solution for approximately 10 seconds and consume contents.
  • Swallow solution at least 30 minutes before the first food, beverage, or medication of the day.
  • Avoid lying down for at least 30 minutes after taking BINOSTO and until after the first food of the day.

BINOSTO effervescent tablets are round, flat-faced, white to off-white tablets, 25 mm in diameter, with beveled edges, with "M" debossed on one side, containing 91.37 mg of alendronate sodium, which is equivalent to 70 mg of free alendronic acid. After dissolution the solution has a pH of 4.8-5.4.

Osteonecrosis of the jaw (ONJ), which can occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing, and has been reported in patients taking bisphosphonates, including alendronate sodium. Known risk factors for osteonecrosis of the jaw include invasive dental procedures (e.g., tooth extraction, dental implants, boney surgery), diagnosis of cancer, concomitant therapies (e.g., chemotherapy, corticosteroids, angiogenesis inhibitors), poor oral hygiene, and co-morbid disorders (e.g., periodontal and/or other pre-existing dental disease, anemia, coagulopathy, infection, ill-fitting dentures). The risk of ONJ may increase with duration of exposure to bisphosphonates.

For patients requiring invasive dental procedures, discontinuation of bisphosphonate treatment may reduce the risk for ONJ. Clinical judgment of the treating physician and/or oral surgeon should guide the management plan of each patient based on individual benefit/risk assessment.

Patients who develop osteonecrosis of the jaw while on bisphosphonate therapy should receive care by an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Discontinuation of bisphosphonate therapy should be considered based on individual benefit/risk assessment.

The following adverse reactions have been identified during post-approval use of alendronate sodium or bisphosphonate products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole: hypersensitivity reactions including urticaria and angioedema. Transient symptoms of myalgia, malaise, asthenia and fever have been reported with alendronate, typically in association with initiation of treatment. Symptomatic hypocalcemia has occurred, generally in association with predisposing conditions. Peripheral edema.

Gastrointestinal: esophagitis, esophageal erosions, esophageal ulcers, esophageal stricture or perforation, and oropharyngeal ulceration. Gastric or duodenal ulcers, some severe and with complications have also been reported [see Dosage and Administration (2.3); Warnings and Precautions (5.1)].

Dental: Localized osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection with delayed healing, has been reported [see Warnings and Precautions (5.4)].

Musculoskeletal: bone, joint, and/or muscle pain, occasionally severe and incapacitating [see Warnings and Precautions (5.3)]; joint swelling; low-energy femoral shaft and subtrochanteric fractures, and atypical fractures of other bones [see Warnings and Precautions (5.5].

Nervous system: dizziness and vertigo.

Pulmonary: acute asthma exacerbations

Skin: rash (occasionally with photosensitivity), pruritus, alopecia, severe skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis.

Special Senses: uveitis, scleritis or episcleritis. Cholesteatoma of the external auditory canal (focal osteonecrosis).

• Pregnancy: Discontinue when pregnancy is recognized. (8.1)
• BINOSTO is not indicated for use in pediatric patients. (8.4)
• BINOSTO is not recommended in patients with renal impairment (creatinine clearance less than 35 mL/min). (5.6, 8.6)

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The safety of BINOSTO (alendronate sodium) effervescent tablet 70 mg is based on clinical trial data of alendronate sodium 10 mg daily and alendronate sodium 70 mg weekly.

The optimal duration of use has not been determined. The safety and effectiveness of BINOSTO for the treatment of osteoporosis are based on clinical data of four years duration. All patients on bisphosphonate therapy should have the need for continued therapy re-evaluated on a periodic basis. Patients at low-risk for fracture should be considered for drug discontinuation after 3 to 5 years of use. Patients who discontinue therapy should have their risk for fracture re-evaluated periodically.

Co-administration of BINOSTO and calcium, antacids, or oral medications containing multivalent cations will interfere with absorption of BINOSTO. Therefore, instruct patients to wait at least one-half hour after taking BINOSTO before taking any other oral medications.

See FDA-approved patient labeling (Medication Guide).

Instruct patients to read the Medication Guide before starting therapy with BINOSTO and to reread it each time the prescription is renewed.

Inform patients who are prescribed sodium restricted diets that BINOSTO contains 603 mg of sodium which is equivalent to approximately 1532 mg NaCl per tablet.

BINOSTO effervescent tablets are round, flat faced, white to off-white tablets with beveled edges and "M" debossed on one side. BINOSTO effervescent tablets, 70 mg are provided in blisters made of aluminum foil composite, as follows:

NDC 70539-400-04 carton containing 4 units of use blisters

Instruct patients to do the following to assure adequate drug absorption and to decrease the risk of esophageal adverse reactions:

• Take BINOSTO upon arising for the day and at least 30 minutes before the first food, beverage, or medication of the day.
• Patients should not swallow the undissolved effervescent tablet, should not chew the effervescent tablet or allow the effervescent tablet to dissolve in their mouths because of the risk for oropharyngeal irritation [see Warnings and Precautions (5.1)].
• Dissolve the effervescent tablet in 4 ounces room temperature plain water only (not mineral water or flavored water).
• Wait at least 5 minutes after the effervescence stops and then stir the buffered solution for approximately 10 seconds and ingest.
• Avoid lying down for at least 30 minutes after taking BINOSTO and until after their first food of the day.
• Do not take BINOSTO at bedtime or before arising for the day.
  
  Failure to follow these instructions may increase the risk of esophageal adverse reactions [see Warnings and Precautions (5.1)].

The relative inhibitory activities on bone resorption and mineralization of alendronate and etidronate were compared in the Schenk assay, which is based on histological examination of the epiphyses of growing rats. In this assay, the lowest dose of alendronate that interfered with bone mineralization (leading to osteomalacia) was 6000-fold the antiresorptive dose. The corresponding ratio for etidronate was one to one. These data suggest that alendronate administered in therapeutic doses is highly unlikely to induce osteomalacia.

BINOSTO, like other bisphosphonates administered orally, may cause local irritation of the upper gastrointestinal mucosa. Because of these possible irritant effects and a potential for worsening of the underlying disease, caution should be used when BINOSTO is given to patients with active upper gastrointestinal problems (such as known Barrett's esophagus, dysphagia, other esophageal diseases, gastritis, duodenitis, or ulcers).

Esophageal adverse experiences, such as esophagitis, esophageal ulcers and esophageal erosions, occasionally with bleeding and rarely followed by esophageal stricture or perforation, have been reported in patients receiving treatment with oral bisphosphonates including alendronate sodium. In some cases these have been severe and required hospitalization. Physicians should therefore be alert to any signs or symptoms signaling a possible esophageal reaction and patients should be instructed to discontinue BINOSTO and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn.

The risk of severe esophageal adverse experiences appears to be greater in patients who lie down after taking oral bisphosphonates including alendronate sodium, and/or who continue to take oral bisphosphonates including alendronate sodium after developing symptoms suggestive of esophageal irritation. Therefore, it is very important that the full dosing instructions are provided to, and understood by, the patient [see Dosage and Administration (2.3)]. In patients who cannot comply with dosing instructions due to mental disability, therapy with BINOSTO should be used under appropriate supervision.

There have been post-marketing reports of gastric and duodenal ulcers with oral bisphosphonate use, some severe and with complications, although no increased risk was observed in controlled clinical trials [see Adverse Reactions (6.2)].

Each BINOSTO effervescent tablet contains 603 mg of sodium, equivalent to approximately 1532 mg of salt (NaCl). Use caution in patients who must restrict their sodium intake, including some patients with a history of heart failure, hypertension, or other cardiovascular diseases [see Patient Counseling Information (17.3)].

Fold and tear at

notch or cut

NDC 70539-400-00

Binosto^®

(alendronate sodium) effervescent

tablet for oral solution

70 mg

Rx only

This blister contains 1 complete week of treatment

2023-BIN-0001

Manufactured for:

Radius Health, Inc.

22 Boston Wharf Road, 7^th Floor

Boston, MA 02210 USA

If the once-weekly dose is missed, instruct patients to take one dose on the morning after they remember. They should not take 2 doses on the same day but should return to taking one dose once a week, as originally scheduled on their chosen day.

BINOSTO may be administered to patients taking NSAIDs. In a 3-year, controlled, clinical study (n=2027) during which a majority of patients received concomitant NSAIDs, the incidence of upper gastrointestinal adverse events was similar in patients taking alendronate sodium 5 or 10 mg/day compared to those taking placebo. However, since NSAID use is associated with gastrointestinal irritation, caution should be used during concomitant use with BINOSTO.

Atypical, low-energy, or low trauma fractures of the femoral shaft have been reported during treatment with bisphosphonates, including alendronate sodium, in patients with osteoporosis. Atypical femur and other fractures most commonly occur with minimal or no trauma to the affected area. These fractures occurred anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. Atypical fractures of other bones have also been reported. They may be bilateral. These fractures can also occur in osteoporotic patients who have not been treated with bisphosphonates. Concomitant treatment with glucocorticoids may also induce these fractures.

Prodromal pain in the affected area, usually presenting as dull, aching pain, weeks to months before a complete fracture occurs was reported by patients.

Any patient with a history of bisphosphonate exposure who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Bone pain in other locations should also be considered for evaluation of atypical fracture. Patients presenting with an atypical fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Risk/benefit of continuing bisphosphonate therapy should be re-evaluated in these patients and interruption of bisphosphonate therapy should be considered.

BINOSTO effervescent tablet 70 mg is indicated for the treatment of osteoporosis in postmenopausal women. For the treatment of osteoporosis, alendronate sodium increases bone mass and reduces the incidence of fractures, including those of the hip and spine (vertebral compression fractures). [See Clinical Studies (14.1).]

The recommended dosage is one 70 mg effervescent tablet once weekly.

BINOSTO (alendronate sodium) effervescent tablet 70 mg is bioequivalent to alendronate sodium tablet 70 mg. The fracture reduction efficacy and bone mineral density changes attributed to BINOSTO are based on clinical trial data of alendronate sodium 10 mg daily and alendronate sodium 70 mg weekly.

NDC 70539-400-04

Rx only

Binosto^®

(alendronate sodium) effervescent

tablet for oral solution

70 mg*

* Each effervescent tablet contains 91.37 mg

alendronate sodium (70 mg free acid equivalent)

4 Effervescent Tablets

ATTENTION PHARMACIST:

Each patient is required to

receive the medication guide.

Harderian gland (a retro-orbital gland not present in humans) adenomas were increased in high-dose female mice (p=0.003) in a 92-week oral carcinogenicity study at doses of alendronate of 1, 3, and 10 mg/kg/day (males) or 1, 2, and 5 mg/kg/day (females). These doses are equivalent to 0.12 to 1.2 times a maximum recommended daily dose of 40 mg, based on surface area, mg/m². The relevance of this finding to humans is unknown.

Parafollicular cell (thyroid) adenomas were increased in high-dose male rats (p=0.003) in a 2-year oral carcinogenicity study at doses of 1 and 3.75 mg/kg body weight. These doses are equivalent to 0.26 and 1 times a 40 mg human daily dose based on surface area, mg/m². The relevance of this finding to humans is unknown.

Alendronate sodium was not genotoxic in the in vitro microbial mutagenesis assay with and without metabolic activation, in an in vitro mammalian cell mutagenesis assay, in an in vitro alkaline elution assay in rat hepatocytes, and in an in vivo chromosomal aberration assay in mice. In an in vitro chromosomal aberration assay in Chinese hamster ovary cells, however, alendronate gave equivocal results.

Alendronate sodium had no effect on fertility (male or female) in rats at oral doses up to 5 mg/kg/day (1.3 times a 40 mg human daily dose based on surface area, mg/m²).

BINOSTO is indicated for treatment to increase bone mass in men with osteoporosis [see Clinical Studies (14.2)].

The recommended dosage is one 70 mg effervescent tablet once weekly.

The efficacy of alendronate sodium in men with hypogonadal or idiopathic osteoporosis was demonstrated in two clinical studies.

Instruct patients to take supplemental calcium and vitamin D if dietary intake is inadequate [see Warnings and Precautions (5.2)]. Patients at increased risk for vitamin D insufficiency (e.g., over the age of 70 years, nursing home-bound, or chronically ill) may need vitamin D supplementation. Patients with gastrointestinal malabsorption syndromes may require higher doses of vitamin D supplementation and measurement of 25-hydroxyvitamin D should be considered.

NDC 70539-400-94

Rx only

SAMPLE—NOT FOR SALE

Binosto^®

(alendronate sodium) effervescent

tablet for oral solution

70 mg*

* Each effervescent tablet contains 91.37 mg

alendronate sodium (70 mg free acid equivalent)

4 Effervescent Tablets

ATTENTION PHARMACIST:

Each patient is required to

receive the medication guide.

Instruct patients to take supplemental calcium and vitamin D, if daily dietary intake is inadequate. Weight-bearing exercise should be considered along with the modification of certain behavioral factors, such as cigarette smoking and/or excessive alcohol consumption, if these factors exist.