Alendronate

Fosamax can cause serious side effects. Call your doctor immediately if you experience any of the following.

Esophagus problems: Fosamax can cause irritation, inflammation, or ulcers of the esophagus which may sometimes bleed.

Taking Fosamax exactly as your doctor prescribes can help lower your chance of having esophagus problems.

If you get chest pain, new or worsening heartburn, or have trouble or pain when you swallow, immediately stop taking Fosamax and call your doctor.

Low calcium levels in your blood (hypocalcemia): Since Fosamax can cause low calcium levels, if you have low blood calcium before you start taking Fosamax, it may get worse during treatment and must be treated before you take Fosamax.

Symptoms of low blood calcium include, spasms; twitches or cramps in your muscles; and numbness or tingling in your fingers, toes, or around your mouth.

Bone, joint, or muscle pain: Fosamax can cause severe bone, joint, or muscle pain.

Severe jaw bone problems (osteonecrosis): Before taking Fosamax, your doctor, and possibly dentist, will examine your mouth.

Fosamax can cause jawbone tissue to break down, exposing the bone and possibly leading to infections, gum lesions and loosened teeth.

Unusual thigh bone fractures: Fosamax can cause fractures in thigh bones. Symptoms of a fracture may include new or unusual pain in your hip, groin, or thigh.

Allergic reactions and asthma: Fosamax can also cause allergic reactions, such as hives or swelling of your face, lips, tongue, or throat, and may worsen asthma symptoms.

Tell your doctor if you are breastfeeding or planning to breastfeed. It is not known if alendronate is excreted in human breast milk or if it will harm your nursing baby.

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

If alendronate is administered by a healthcare provider in a medical setting, it is unlikely that an overdose will occur. However, if overdose is suspected, seek emergency medical attention.

Avoid taking any other medicines including vitamins, calcium, or antacids for at least 30 minutes after taking alendronate. Some medicines can make it harder for your body to absorb alendronate.

Usual Adult Dose for Osteoporosis:

Treatment of Osteoporosis in Postmenopausal Women; To Increase Bone Mass in Men with Osteoporosis:
-10 mg orally once a day or
-70 mg orally once a week

Treatment of Glucocorticoid-Induced Osteoporosis:
-5 mg orally once a day or
-10 mg orally once a day in postmenopausal women not receiving estrogen

Comments:
-Refer to administration advice for details on how to take this drug.
-Reevaluate bisphosphonate therapy periodically.

Uses:
-Treatment to increase bone mass and reduce the incidence of fractures including hip and spine (vertebral compression fractures) in postmenopausal women with osteoporosis
-Treatment to increase bone mass in men with osteoporosis
-Treatment of glucocorticoid-induced osteoporosis in men and women receiving glucocorticoids in a daily dosage equivalent to 7.5 mg or greater of prednisone and who have low bone mineral density

Usual Adult Dose for Prevention of Osteoporosis:

-5 mg orally once a day or
-35 mg orally once a week

Comments:
-Refer to administration advice for details on how to take this drug.
-Reevaluate bisphosphonate therapy periodically.

Use: Prevention of osteoporosis in postmenopausal women

Usual Adult Dose for Paget's Disease:

-40 mg orally once a day for six months

Comments:
-Retreatment may be considered, following a six- month post-treatment evaluation period in patients who have relapsed, based on increases in serum alkaline phosphatase measured periodically.
-Retreatment may also be considered in patients who failed to normalize serum alkaline phosphatase.

Use: Treatment of Paget's disease of bone

● 35 mg tablets are white to off-white oval tablet embossed with “AN35" on one side and “” on the other side.

● 70 mg tablets are white to off-white oval tablet embossed with “AN70" on one side and “” on the other side.

Pregnancy

Pregnancy Category C:
There are no studies in pregnant women. Alendronate sodium should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and fetus.

Bisphosphonates are incorporated into the bone matrix, from which they are gradually released over a period of years. The amount of bisphosphonate incorporated into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the dose and duration of bisphosphonate use. There are no data on fetal risk in humans. However, there is a theoretical risk of fetal harm, predominantly skeletal, if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on the risk has not been studied.

Reproduction studies in rats showed decreased postimplantation survival and decreased body weight gain in normal pups at doses less than half of the recommended clinical dose. Sites of incomplete fetal ossification were statistically significantly increased in rats beginning at approximately 3 times the clinical dose in vertebral (cervical, thoracic, and lumbar), skull, and sternebral bones. No similar fetal effects were seen when pregnant rabbits were treated with doses approximately 10 times the clinical dose.

Both total and ionized calcium decreased in pregnant rats at approximately 4 times the clinical dose resulting in delays and failures of delivery. Protracted parturition due to maternal hypocalcemia occurred in rats at doses as low as one tenth the clinical dose when rats were treated from before mating through gestation. Maternotoxicity (late pregnancy deaths) also occurred in the female rats treated at approximately 4 times the clinical dose for varying periods of time ranging from treatment only during pre-mating to treatment only during early, middle, or late gestation; these deaths were lessened but not eliminated by cessation of treatment. Calcium supplementation either in the drinking water or by minipump could not ameliorate the hypocalcemia or prevent maternal and neonatal deaths due to delays in delivery; intravenous calcium supplementation prevented maternal, but not fetal deaths.

Exposure multiples based on surface area, mg/m2, were calculated using a 40-mg human daily dose. Animal dose ranged between 1 and 15 mg/kg/day in rats and up to 40 mg/kg/day in rabbits.

Nursing Mothers

It is not known whether Alendronate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Alendronate sodium is administered to nursing women.

Pediatric Use

Alendronate sodium 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 to 18 years, with severe osteogenesis imperfecta (OI). One-hundred-and-nine patients were randomized to 5 mg Alendronate daily (weight less than  40 kg) or 10 mg Alendronate 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 sodium-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 sodium 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 sodium-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 35 mg 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).]

Geriatric Use

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, osteoporosis studies in men, glucocorticoid-induced osteoporosis studies, and Paget’s disease studies [see Clinical Studies (14.1), (14.3), (14.4), (14.5)], 45%, 54%, 37%, and 70%, 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.

Renal Impairment

Alendronate sodium 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 to 60 mL/min [see Clinical Pharmacology (12.3)].

Hepatic Impairment

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)].

• Bisphosphonate Derivative

Hypersensitivity to alendronate, other bisphosphonates, or any component of the formulation; hypocalcemia; abnormalities of the esophagus (eg, stricture, achalasia) which delay esophageal emptying; inability to stand or sit upright for at least 30 minutes; increased risk of aspiration (effervescent tablets; oral solution)

Canadian labeling: Additional contraindications (not in US labeling): Renal insufficiency with creatinine clearance <35 mL/minute

Aminoglycosides: May enhance the hypocalcemic effect of Bisphosphonate Derivatives. Monitor therapy

Antacids: May decrease the serum concentration of Bisphosphonate Derivatives. Management: Avoid administration of antacids containing polyvalent cations within: 2 hours before or after tiludronate/clodronate/etidronate; 60 minutes after oral ibandronate; or 30 minutes after alendronate/risedronate. Exceptions: Magaldrate; Sodium Bicarbonate. Consider therapy modification

Aspirin: May enhance the adverse/toxic effect of Alendronate. Specifically, the incidence of upper gastrointestinal adverse events may be increased Monitor therapy

Calcium Salts: May decrease the serum concentration of Bisphosphonate Derivatives. Management: Avoid administration of oral calcium supplements within: 2 hours before or after tiludronate/clodronate/etidronate; 60 minutes after oral ibandronate; or 30 minutes after alendronate/risedronate. Consider therapy modification

Deferasirox: Bisphosphonate Derivatives may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Monitor therapy

Iron Salts: May decrease the serum concentration of Bisphosphonate Derivatives. Management: Avoid administration of oral iron supplements within: 2 hours before or after tiludronate/clodronate/etidronate; 60 minutes after oral ibandronate; or 30 minutes after alendronate/risedronate. Exceptions: Ferric Carboxymaltose; Ferric Gluconate; Ferric Hydroxide Polymaltose Complex; Ferric Pyrophosphate Citrate; Ferumoxytol; Iron Dextran Complex; Iron Sucrose. Consider therapy modification

Magnesium Salts: May decrease the serum concentration of Bisphosphonate Derivatives. Management: Avoid administration of oral magnesium salts within: 2 hours before or after tiludronate/clodronate/etidronate; 60 minutes after oral ibandronate; or 30 minutes after alendronate/risedronate. Consider therapy modification

Multivitamins/Minerals (with ADEK, Folate, Iron): May decrease the serum concentration of Bisphosphonate Derivatives. Specifically, polyvalent cation-containing multivitamins may decrease the absorption of orally-administered bisphosphonate derivatives. Management: Avoid administration of polyvalent cation-containing multivitamins within: 2 hours before or after tiludronate/clodronate/etidronate; 60 minutes after oral ibandronate; or 30 minutes after alendronate/risedronate. Consider therapy modification

Multivitamins/Minerals (with AE, No Iron): May decrease the serum concentration of Bisphosphonate Derivatives. Specifically, polyvalent cation-containing multivitamins may decrease the absorption of orally-administered bisphosphonate derivatives. Management: Avoid administration of polyvalent cation-containing multivitamins within: 2 hours before or after tiludronate/clodronate/etidronate; 60 minutes after oral ibandronate; or 30 minutes after alendronate/risedronate. Consider therapy modification

Nonsteroidal Anti-Inflammatory Agents: May enhance the adverse/toxic effect of Bisphosphonate Derivatives. Both an increased risk of gastrointestinal ulceration and an increased risk of nephrotoxicity are of concern. Monitor therapy

Parathyroid Hormone: Alendronate may diminish the therapeutic effect of Parathyroid Hormone. More specifically, Alendronate may interfere with normalization of blood calcium concentrations. Avoid combination

Proton Pump Inhibitors: May diminish the therapeutic effect of Bisphosphonate Derivatives. Monitor therapy

Systemic Angiogenesis Inhibitors: May enhance the adverse/toxic effect of Bisphosphonate Derivatives. Specifically, the risk for osteonecrosis of the jaw may be increased. Monitor therapy

Note: Incidence of adverse effects (mostly GI) increases significantly in patients treated for Paget's disease at 40 mg/day.

>10%: Endocrine & metabolic: Decreased serum calcium (18%; transient, mild)

1% to 10%:

Central nervous system: Headache (3%)

Endocrine & metabolic: Decreased serum phosphate (10%; transient, mild)

Gastrointestinal: Abdominal pain (2% to 7%), acid regurgitation (1% to 5%), flatulence (≤4%), gastroesophageal reflux disease (3%), constipation (≤3%), diarrhea (≤3%), dyspepsia (1% to 3%), nausea (1% to 3%), esophageal ulcer (2%), dysphagia (1%), melena (1%), abdominal distension (≤1%), gastric ulcer (≤1%; may be severe with complications), gastritis (≤1%)

Neuromuscular & skeletal: Musculoskeletal pain (≤6%; includes bone pain, joint pain, and muscle pain), muscle cramps (≤1%)

<1% (Limited to important or life-threatening): Alopecia, cholesteatoma, conjunctivitis, duodenal ulcer (may be severe with complications), dysgeusia, episcleritis, erythema, erosive esophagitis, esophageal perforation, esophageal stenosis, esophageal ulcer, esophagitis, exacerbation of asthma, femur fracture (low energy fractures, including subtrochanteric and diaphyseal), hypersensitivity reaction (includes angioedema and urticaria), hypocalcemia (symptomatic), joint swelling, malaise, oropharyngeal ulcer, osteonecrosis of the jaw (generally associated with tooth extraction and/or local infection with delayed healing), peripheral edema, scleritis, skin rash (occasionally with photosensitivity), Stevens-Johnson syndrome, toxic epidermal necrolysis, uveitis, vertigo, weakness

Mechanism of Action

Bisphosphonate; binds to hydroxyapatite crystals in bone and inhibits osteoclast-mediated bone resorption; decreases mineral release and collagen or matrix breakdown in bone

Absorption

Bioavailability (fasting): Women, 0.64%; men, 0.59%; reduced up to 60% by food

Onset: 3 weeks

Duration: 12-30 weeks (multiple doses)

Distribution

Protein bound: 78%

Vd: 28 L (exclusive of bone)

Metabolism

Not metabolized

Elimination

Half-life: Up to 10 years in bone (terminal)

Excretion: Urine 50%, feces (unabsorbed drug)

Commonly reported side effects of alendronate include: decreased serum calcium and decreased serum phosphate. Other side effects include: arthralgia, myalgia, and ostealgia. See below for a comprehensive list of adverse effects.

No adjustment recommended.

• Take alendronate at least 30 minutes before eating or drinking any food or beverages (other than water), or taking any other medication, including calcium, antacids or vitamins for the day.
• Take alendronate with a full glass of water and remain upright for at least 30 minutes. Do not lie down. Do not substitute water with mineral water, coffee, soda, juice or tea. Never take alendronate at bedtime.
• Avoid eating, drinking (other than water) or taking other medications for 30 minutes after taking alendronate.
• Dissolve alendronate effervescent tablets in 4oz of room temperature tap water. Wait 5 minutes after effervescence stops before stirring for 10 seconds then drinking.
• You may need to take supplementary calcium or vitamin D if your dietary intake is inadequate. Your doctor will advise you on this. If you are taking supplemental calcium, iron, magnesium, or antacids, take them at a different time of day to alendronate (for example at lunchtime), as they may interfere with the absorption of alendronate.
• Talk to both your dentist and doctor if you require dental surgery or a tooth extraction and you have been on alendronate long-term. They may advise discontinuation of alendronate.
• Tell your doctor if you experience any thigh or groin pain, severe or debilitating muscle pain, eye inflammation, or any other adverse effects of concern while you are taking alendronate.

Summary of Use during Lactation

Limited evidence indicates that breastfeeding after cessation of long-term bisphosphonate treatment appears to have no adverse effects on the infant. Because no information is available on the use of alendronate during breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or preterm infant. However, absorption of alendronate by a breastfed infant is unlikely. If the mother receives a bisphosphonate during pregnancy or nursing, some experts recommend monitoring the infant's serum calcium during the first 2 months postpartum.[1]

Drug Levels

Alendronate is poorly absorbed orally (average in adults 1% on an empty stomach, negligible with food and calcium), so absorption of alendronate by a breastfed infant is unlikely. Maternal Levels. Relevant published information was not found as of the revision date.

Infant Levels. Relevant published information was not found as of the revision date.

Effects in Breastfed Infants

Because alendronate can persist in the body for years after long-term administration, the following cases may be relevant. A woman received alendronate for 6 months, then pamidronate every 4 months for 1 year prior to conception. Her infant was breastfed (extent not stated) for 3 months. The infant had mild hypocalcemia at 2 months of age, but a normal calcium level and normal long bone development at 5 months of age.[2]

Effects on Lactation and Breastmilk

Relevant published information was not found as of the revision date.

Alternate Drugs to Consider

Pamidronate

References

1. Stathopoulos IP, Liakou CG, Katsalira A et al. The use of bisphosphonates in women prior to or during pregnancy and lactation. Hormones. 2011;10:280-91. PMID: 22281884

2. Hassen-Zrour S, Korbaa W, Bejia I et al. Maternal and fetal outcome after long-term bisphosphonate exposure before conception. Osteoporos Int. 2010;21:709-10. PMID: 19533208