Etidronate Disodium

Class: Bone Resorption Inhibitors
VA Class: HS900
CAS Number: 7414-83-7
Brands: Didronel

Special Alerts:

[Posted 07/21/2011] ISSUE: FDA notified healthcare professionals and patients about its ongoing review of data from published studies to evaluate whether use of oral bisphosphonate drugs is associated with an increased risk of cancer of the esophagus. FDA has not concluded that taking an oral bisphosphonate drug increases the risk of esophageal cancer. There are insufficient data to recommend endoscopic screening of asymptomatic patients. FDA will continue to evaluate all available data supporting the safety and effectiveness of bisphosphonate drugs and will update the public when more information becomes available.

BACKGROUND: Oral bisphosphonates are commonly used for the prevention and treatment of osteoporosis as well as to treat other bone diseases such as Paget’s disease. There have been conflicting findings from studies evaluating the risk of esophageal cancer. Esophagitis and other esophageal events have been reported, particularly in patients who do not follow the specific directions for use of oral bisphosphonates. See the Data Summary in the Drug Safety Communication for additional details at: .

RECOMMENDATION: Patients should talk with their healthcare professional about the benefits and risks of taking oral bisphosphonates and how long they should expect to take them. Patients should talk with their healthcare professional if they develop swallowing difficulties, chest pain, new or worsening heartburn, or have trouble or pain when swallowing. Patients should be instructed to carefully follow the directions for use of the oral bisphosphonate drug they are prescribed. For more information visit the FDA website at: and .

[Posted 10/13/2010] ISSUE: FDA is updating the public regarding information previously communicated describing the risk of atypical fractures of the thigh, known as subtrochanteric and diaphyseal femur fractures, in patients who take bisphosphonates for osteoporosis. This information will be added to the Warnings and Precautions section of the labels approved to treat osteoporosis, including alendronate (Fosamax), alendronate with cholecalciferol (Fosamax Plus D), risedronate (Actonel and Atelvia), risedronate with calcium carbonate (Actonel with Calcium), ibandronate (Boniva), tiludronate (Skelid), and zoledronic acid (Reclast) and their generic products. A Medication Guide will also be required to be given to patients when they pick up their bisphosphonate prescription.

BACKGROUND: Atypical subtrochanteric femur fractures are fractures in the bone just below the hip joint. Diaphyseal femur fractures occur in the long part of the thigh bone. These fractures are very uncommon and appear to account for less than 1% of all hip and femur fractures overall. Although it is not clear if bisphosphonates are the cause, these unusual femur fractures have been predominantly reported in patients taking bisphosphonates.

RECOMMENDATIONS: Patients should continue to take their medication unless told to stop by their healthcare professional. FDA recommends that healthcare professionals should discontinue potent antiresorptive medications (including bisphosphonates) in patients who have evidence of a femoral shaft fracture. For more information visit the FDA website at: and .

[Posted 03/11/2010] FDA notified healthcare professionals and patients that at this point, the data that FDA has reviewed have not shown a clear connection between bisphosphonate use and a risk of atypical subtrochanteric femur fractures. FDA is working with outside experts, including members of the recently convened American Society of Bone and Mineral Research Subtrochanteric Femoral Fracture Task Force, to gather more information and evaluate the issue further.

FDA recommends that healthcare professionals follow the recommendations in the drug label when prescribing oral bisphosphonates.

Patients should continue taking oral bisphosphonates unless told by their healthcare professional to stop. Patients should talk to their healthcare professional if they develop new hip or thigh pain or have any concerns with their medications. For more information visit the FDA website at: and .

[Posted 11/12/2008] FDA issued an update to the Agency’s review of safety data regarding the potential increased risk of atrial fibrillation in patients treated with a bisphosphonate drug. Bisphosphonates are a class of drugs used primarily to increase bone mass and reduce the risk for fracture in patients with osteoporosis, slow bone turnover in patients with Paget’s disease of the bone, and to treat bone metastases and lower elevated levels of blood calcium in patients with cancer. FDA reviewed data on 19,687 bisphosphonate-treated patients and 18,358 placebo-treated patients who were followed for 6 months to 3 years. The occurrence of atrial fibrillation was rare within each study, with most studies containing 2 or fewer events. Across all studies, no clear association between overall bisphosphonate exposure and the rate of serious or non-serious atrial fibrillation was observed. Additionally, increasing dose or duration of bisphosphonate therapy was not associated with an increase rate of atrial fibrillation. Healthcare professionals should not alter their prescribing patterns for bisphosphonates and patients should not stop taking their bisphosphonate medication. For more information visit the FDA website at: , and .

[Posted 01/07/2008] FDA informed healthcare professionals and patients of the possibility of severe and sometimes incapacitating bone, joint, and/or muscle (musculoskeletal) pain in patients taking bisphosphonates. Although severe musculoskeletal pain is included in the prescribing information for all bisphosphonates, the association between bisphosphonates and severe musculoskeletal pain may be overlooked by healthcare professionals, delaying diagnosis, prolonging pain and/or impairment, and necessitating the use of analgesics. The severe musculoskeletal pain may occur within days, months, or years after starting a bisphosphonates. Some patients have reported complete relief of symptoms after discontinuing the bisphosphonate, whereas others have reported slow or incomplete resolution. The risk factors for and incidence of severe musculoskeletal pain associated with bisphosphonates are unknown.

Healthcare professionals should consider whether bisphosphonate use might be responsible for severe musculoskeletal pain in patients who present with these symptoms and consider temporary or permanent discontinuation of the drug. For more information visit the FDA website at: and .

[Posted 10/01/2007] FDA issued an early communication about the ongoing review of new safety data regarding the association of atrial fibrillation with the use of bisphosphonates. Bisphosphonates are a class of drugs used primarily to increase bone mass and reduce the risk for fracture in patients with osteoporosis, slow bone turnover in patients with Paget’s disease of the bone, treat bone metastases, and lower elevated levels of blood calcium in patients with cancer.

FDA reviewed spontaneous postmarketing reports of atrial fibrillation reported in association with oral and intravenous bisphosphonates and did not identify a population of bisphosphonate users at increased risk of atrial fibrillation. In addition, as part of the data review for the recent approval of once-yearly Reclast for the treatment of postmenopausal osteoporosis, FDA evaluated the possible association between atrial fibrillation and the use of Reclast (zoledronic acid). Most cases of atrial fibrillation occurred more than a month after drug infusion. Also, in a subset of patients monitored by electrocardiogram up to the 11th day following infusion, there was no significant difference in the prevalence of atrial fibrillation between patients who received Reclast and patients who received placebo.

Upon initial review, it is unclear how these data on serious atrial fibrillation should be interpreted. Therefore, FDA does not believe that healthcare providers or patients should change either their prescribing practices or their use of bisphosphonates at this time. For more information visit the FDA website at: and .

Introduction

Synthetic bisphosphonate; bone resorption inhibitor.^c

Uses for Etidronate Disodium

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Paget’s Disease of Bone

Used in the treatment of moderate to severe symptomatic Paget’s disease of bone (osteitis deformans). ^{131 132 141 142 143 144 145 146 b}

Efficacy not established in asymptomatic patients.^b May consider prophylactic treatment in patients with extensive involvement of the skull or spinal column and the possibility of irreversible neurologic damage or in those with extensive involvement threatening major joints or weight-bearing bones.^{b c}

Less effective than risedronate or alendronate in the treatment of moderate to severe Paget’s disease of bone.^{128 129 d}

Relapse generally tends to occur within about 3–24 months in patients most likely to relapse (e.g., higher pretreatment markers of bone turnover).^c

Resistance is most likely to develop in patients receiving >1 course of therapy per year or those with higher pretreatment indices of bone turnover.¹⁰⁷

Heterotopic Ossification

Used in the prevention and treatment of heterotopic ossification (myositis ossificans, ectopic calcification, periarticular ossification, or paraosteoarthropathy) following total hip arthroplasty or resulting from spinal cord injury.^b

Efficacy not established for treatment of idiopathic heterotopic ossification† or heterotopic ossification associated with conditions other than total hip arthroplasty or spinal cord injury†.^c

Corticosteroid-induced Osteoporosis

Bisphosphonates, including etidronate, have been used effectively for the prevention and treatment of corticosteroid-induced osteoporosis†.^{131 132 133 134 135 136 137 139 141 142 143 144 145 146} American College of Rheumatology (ACR) recommends alendronate or risedronate therapy in men, premenopausal women (with caution), and postmenopausal women receiving long-term corticosteroid therapy (≥5 mg of prednisone or equivalent dosage daily for ≥3 months).¹³⁹

Postmenopausal Osteoporosis

Bisphosphonates, including etidronate, have been used for the treatment of postmenopausal osteoporosis† and are recommended by the North American Menopause Society for this use.^a However, the American College of Obstetricians and Gynecologists (ACOG) recommends alendronate and risedronate as first-line agents for the treatment of osteoporosis.^f

Etidronate Disodium Dosage and Administration

General

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Paget’s Disease of Bone

• 
  

  Monitor patients for recurrence of disease every 3–6 months.^b Consider retreatment only after a drug-free interval of ≥90 days following the previous course of therapy if biochemical, symptomatic, or other evidence of recurrence is present.^b

  
  

Heterotopic Ossification

• 
  

  Initiate therapy as soon as it is feasible following spinal cord injury and preferably before any radiographic evidence of heterotopic ossification.^b Efficacy of retreatment has not been established in these patients nor in patients undergoing total hip arthroplasty.^b

  
  

Administration

Oral Administration

Administer as a single daily dose; may divide dosage if adverse GI effects occur.^b May be given with water or fruit juice.^c

Avoid food, especially food rich in calcium, vitamins with mineral supplements, or antacids that contain metals such as calcium, iron, magnesium, or aluminum for 2 hours before and after administration.^{b c} (See Food under Pharmacokinetics.)

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Available as etidronate disodium; dosage expressed in terms of the salt.^b

Adults

Paget’s Disease of Bone

Oral

Initially, 5–10 mg/kg daily for ≤6 months, or 11–20 mg/kg daily for ≤3 months, have been used.^b Recommended initial dosage is 5 mg/kg daily for ≤6 months.^b

Onset of therapeutic response may be delayed,^b and therapeutic effects may persist for months following a course of therapy.^b (See Onset under Pharmacokinetics.) Avoid premature increases in dosage^b since increased dosage may cause mineralization defects.^{b c}

Patients who require immediate suppression of Paget’s disease or in whom lower dosages are ineffective: >10 mg/kg daily for ≤3 months.^b Use with caution.^c

Dosages >20 mg/kg daily not recommended.^b

Retreatment: Dosage usually the same as initial treatment.^b Consider increasing dosage within the recommended range if inadequate response with original dosage.^b (See General: Paget’s Disease of Bone under Dosage and Administration.)

Heterotopic Ossification

Prevention and Treatment

Oral

Spinal cord injury: Initially, 20 mg/kg daily for 2 weeks followed by 10 mg/kg daily for an additional 10 weeks (12 weeks total).^b

Total hip arthroplasty: Initially, 20 mg/kg daily administered preoperatively for 1 month and postoperatively for an additional 3 months (4 months total).^b

Corticosteroid-Induced Osteoporosis†

Prevention and Treatment

Oral

400 mg daily for 2 weeks every 3 months has been used, usually in conjunction with calcium (e.g., 500 mg daily) and vitamin D supplementation during the remaining 10–11 weeks of each cycle or continuously.^{141 142 143 144 145 146 147}

Administer for as long as corticosteroid therapy continues.¹³⁹

Postmenopausal Osteoporosis†

Treatment

Oral

400 mg daily for 14 days every 3 months has been used, in conjunction with calcium supplementation during the last 10 weeks of each cycle.^a

Prescribing Limits

Adults

Paget’s Disease of Bone

Oral

Maximum 20 mg/kg daily.^b

Treatment duration: ≤6 months; continuous therapy for >6 months may increase the risk of fracture and osteomalacia.^b

Special Populations

Renal Impairment

Reduce dosage in patients with reduced glomerular filtration; monitor such patients closely.¹²⁵

Geriatric Patients

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.^b

Cautions for Etidronate Disodium

Contraindications

• 
  

  Known hypersensitivity to etidronate disodium.¹²⁵

  
  


• 
  

  Clinically overt osteomalacia.¹²⁵

  
  

Warnings/Precautions

Warnings

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity and stillbirths demonstrated in animals.^b

Theoretical risk to fetus exists if pregnancy occurs after completing a course of bisphosphonate therapy.¹²⁵ Impact of variables such as time between cessation of bisphosphonate therapy to conception, particular bisphosphonate used, and route of administration (IV versus oral) on this risk not established.^{125 b}

General Precautions

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Metabolic Effects

Maintain an adequate intake of calcium and vitamin D during therapy.^b

Hyperphosphatemia may occur, especially with dosages of 10–20 mg/kg daily.¹²⁵ (See Actions.) Usually returns to pretreatment values 2–4 weeks after treatment discontinuance.¹²⁵

GI Effects

Therapy has been withheld in some patients with enterocolitis, since diarrhea may occur, especially with high dosages.¹²⁵

Musculoskeletal Effects

Impairs mineralization of new osteoid, principally in pagetic lesions and to a lesser extent in normal bone at dosages of 10–20 mg/kg daily.^{b c} Also may delay mineralization of ectopic bone.^c Mineralization occurs normally following completion of therapy.^b

Long bones affected mainly by lytic pagetic lesions, particularly in patients whose disease is unresponsive to therapy, may be especially prone to fractures.^b Monitor patients with predominantly lytic lesions closely, both radiographically and biochemically, to permit timely discontinuance of therapy in those whose disease is unresponsive.^b If fractures occur, may be advisable to delay or withhold therapy until callus is evident.^b

Osteonecrosis and osteomyelitis of the jaws have been reported principally in cancer patients receiving bisphosphonates.^{147 148 149 150 151 b} Most cases were associated with dental procedures (e.g., tooth extraction), but some cases occurred in patients with postmenopausal osteoporosis† or other diagnoses.^b Most instances of osteonecrosis of the jaw occurred with IV bisphosphonate therapy, but can occur with oral therapy.^b

Dental examination with appropriate preventive dentistry recommended prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g., cancer, chemotherapy, corticosteroids, poor oral hygiene).ⁱ Avoid invasive dental procedures if possible during therapy in such patients.ⁱ In patients requiring dental procedures, no data are available to suggest whether discontinuance of therapy prior to procedure reduces the risk of osteonecrosis of the jaw.^{b d} Base management of patients requiring dental treatment on an individual assessment of risks and benefits.^{b d}

Severe, occasionally incapacitating bone, joint, and/or muscle pain reported infrequently with bisphosphonate therapy.^{b d} The time to the onset of symptoms varied from 1 day to several months after treatment initiation.^{b d} Such pain improves following discontinuance and may recur upon subsequent rechallenge with the same drug or another bisphosphonate.^{b d}

Specific Populations

Pregnancy

Category C.^b (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether etidronate is distributed into milk.^b Use with caution.^b

Pediatric Use

Safety and efficacy in children not established.^b Has been used in children for the prevention of heterotopic ossification or soft tissue calcification at weight-adjusted dosages recommended for adults.^b

Rachitic syndrome reported infrequently in children receiving dosages of ≥10 mg/kg daily for approximately 1 year or longer.^b Epiphyseal radiographic changes associated with retarded mineralization of new osteoid and cartilage and associated occasional symptoms were reversible following discontinuance of the drug.^b

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults; select dosage with caution.¹²⁵ (See Geriatric Patients under Dosage and Administration.)

Possible age-related impaired renal function and risk of toxic reactions; use with care.¹²⁵ (See Renal Impairment under Cautions and under Dosage and Administration.)

Renal Impairment

Monitor patients with impaired renal function carefully.^{100 125} (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Paget’s disease of bone: Bone pain, diarrhea, nausea.^b

Heterotopic ossification: Diarrhea, nausea.^b

Interactions for Etidronate Disodium

Specific Drugs

Drug	Interaction	Comments
Warfarin	Increases in PT, mostly without clinically important sequelae125	Monitor PT when etidronate added to therapy125

Etidronate Disodium Pharmacokinetics

Absorption

Bioavailability

Approximately 3% of a dose is absorbed.¹²⁵

Onset

Paget’s disease of bone: Reduced urinary excretion of hydroxyproline occurs after 1–3 months of therapy.^c Reductions in markers of bone turnover reach a plateau in about 6 months.^c

Duration

Paget’s disease of bone: May persist for ≥1 year following discontinuance of therapy.^b In patients whose disease is most likely to relapse, relapse generally tends to occur within about 3–24 months.^c

Heterotropic ossification: Persists for ≥9 months following drug discontinuance.^b

Food

Food decreases extent of absorption.^c

Distribution

Extent

Following oral administration, about 50% of absorbed drug distributed almost exclusively into bone.^{b c} Eliminated slowly (weeks to years) via bone turnover.^{100 101 106 b}

Drug does not cross blood-brain barrier in animals.¹²⁵

Not known whether etidronate is distributed into milk.^b

Elimination

Metabolism

No evidence of metabolism.¹²⁵

Elimination Route

Excreted unchanged in urine (approximately half of an absorbed dose)¹⁰¹ within 24 hours.¹²⁵ Unabsorbed drug is excreted intact in feces.^b

Half-life

Plasma elimination half-life is 1–6 hours.¹²⁵ Terminal half-life estimated to be 394 days.^h

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).^b

Actions

• 
  

  Adsorbs to hydroxyapatite crystals and their amorphous precursors in bone matrix and inhibits their aggregation, growth, mineralization, and dissolution.^{b c}

  
  


• 
  

  Heterotopic ossification: Prevents or slows the formation of heterotopic bone during the active stage.^{b c}

  
  


• 
  

  Paget’s disease of bone: Reduces the number of osteoclasts and osteoblasts.^b

  
  


• 
  

  Paget’s disease of bone: Reduces rate of bone turnover as evidenced by decreases in markers of bone turnover and reduced radionuclide uptake at pagetic lesions.^{b c}

  
  


• 
  

  Paget’s disease of bone: Reduces vascularity of pagetic bone, skin temperature over superficially located pagetic lesions, and cardiac output.^{b c}

  
  


• 
  

  Can increase serum phosphate concentration by increasing renal tubular reabsorption of phosphate.^{b c}

  
  


• 
  

  No immunosuppressive activity in animal studies.¹⁰⁴

  
  

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

• 
  

  Importance of proper administration (e.g., avoiding food, vitamins with mineral supplements, or antacids that contain metals for 2 hours before and after administration).^b

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.^b

  
  


• 
  

  Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.^b

  
  


• 
  

  Importance of informing patients of other important precautionary information.^b (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Etidronate Disodium

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets	200 mg	Didronel	Procter & Gamble
		400 mg	Didronel (scored)	Procter & Gamble

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 08/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Didronel 400MG Tablets (WARNER CHILCOTT PHARMA): 30/$226.78 or 90/$643.61

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions July 22, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

Only references cited for selected revisions after 1984 are available electronically.

100. MGI Pharma. Didronel I.V. Infusion (etidronate disodium) prescribing information. Minnetonka, MN; 1998 Jan.

101. Norwich Eaton Pharmaceuticals, Inc. Didronel I.V. Infusion (etidronate disodium) background data for review by pharmacy and therapeutic committees. Publication No. 2326-70. Norwich, NY; 1987 Apr.

102. Kanis JA, Urwin GH, Gray RES et al. Effects of intravenous etidronate disodium on skeletal and calcium metabolism. Am J Med. 1987; 82(Suppl 2A):55-70. [IDIS 227717] [PubMed 3103437]

103. Guaitani A, Polentarutti N, Filippeschi S et al. Effects of disodium etidronate in murine tumor models. Eur J Cancer Clin Oncol. 1984; 20:685-93. [PubMed 6428894]

104. Garattini S, Guaitani A, Mantovani A. Effect of etidronate disodium on the interactions between malignancy and bone. Am J Med. 1987; 82(Suppl 2A):29-33. [IDIS 227713] [PubMed 3103435]

105. Jacobs TP, Gordon AC, Silverberg SJ et al. Neoplastic hypercalcemia: physiologic response to intravenous etidronate disodium. Am J Med. 1987; 82(Suppl 2A):42-50. [IDIS 227715] [PubMed 3030098]

106. Powell JH, DeMark BR. Clinical pharmacokinetics of diphosphonates. In: Garattini S, ed. Bone resorption, metastasis, and diphosphonates. New York: Raven Press; 1985:41-9.

107. Altman RD. Long-term follow-up of therapy with intermittent etidronate disodium in Paget’s disease of bone. Am J Med. 1985; 79:583-90. [IDIS 207333] [PubMed 3933343]

108. Perry HM III, Droke DM, Avioli LV. Alternate calcitonin and etidronate disodium therapy for Paget’s bone disease. Arch Intern Med. 1984; 144:929-33. [IDIS 184749] [PubMed 6424594]

109. Charhon S, Chapuy MC, Valentin-Opran A et al. Intravenous etidronate for spinal cord dysfunction due to Paget’s disease. Lancet. 1982; 1:391-2. [IDIS 144906] [PubMed 6120363]

110. Meunier PJ, Chapuy MC, Delmas P et al. Intravenous disodium etidronate therapy in Paget’s disease of bone and hypercalcemia of malignancy: effects on biochemical parameters and bone histomorphometry. Am J Med. 1987; 82(Suppl 2A):71-8. [IDIS 227718] [PubMed 3103438]

111. Ryzen E, Martodam RR, Troxell M et al. Intravenous etidronate in the management of malignant hypercalcemia. Arch Intern Med. 1985; 145:449-52. [IDIS 197140] [PubMed 3919667]

112. Hasling C, Charles P, Mosekilde L. Etidronate disodium for treating hypercalcaemia of malignancy: a double blind, placebo-controlled study. Eur J Clin Invest. 1986; 16:433-7. [PubMed 3100312]

113. Zweig JI, Shafer N. Treatment of hypercalcemia with etidronate disodium. JAMA. 1980; 244:437-8. [IDIS 125509] [PubMed 6771418]

114. Mundy GR, Wilkinson R, Heath DA. Comparative study of available medical therapy for hypercalcemia of malignancy. Am J Med. 1983; 74:421-32. [IDIS 168018] [PubMed 6219578]

115. Ringenberg QS, Ritch PS. Efficacy of oral administration of etidronate disodium in maintaining normal serum calcium levels in previously hypercalcemic cancer patients. Clin Ther. 1987; 9:318-25. [PubMed 3111705]

116. Schiller JH, Rasmussen P, Benson AB III et al. Maintenance etidronate in the prevention of malignancy-associated hypercalcemia. Arch Intern Med. 1987; 147:963-6. [IDIS 229062] [PubMed 3107487]

117. Hagg E, Eklund M, Torring O. Disodium etidronate in hypercalcaemia due to immobilisation. BMJ. 1984; 288:607-8. [IDIS 182308] [PubMed 6421398]

118. Merli GJ, McElwain GE, Adler AG et al. Immobilization hypercalcemia in acute spinal cord injury treated with etidronate. Arch Intern Med. 1984; 144:1286-8. [IDIS 186433] [PubMed 6428341]

119. Meythaler JM, Korkor AB, Nanda T et al. Immobilization hypercalcemia associated with Landry-Guillain-Barré syndrome: successful therapy with combined calcitonin and etidronate. Arch Intern Med. 1986; 146:1567-71. [IDIS 219423] [PubMed 3089187]

120. Anon. Medical management of primary hyperparathyroidism. Lancet. 1984; 2:727-8. [PubMed 6148476]

121. Licata AA, O’Hanlon E. Treatment of hyperparathyroidism with etidronate disodium. JAMA. 1983; 249:2063-4. [PubMed 6403720]

122. Scher HI, Yagoda A. Bone metastases: pathogenesis, treatment, and rationale for use of resorption inhibitors. Am J Med. 1987; 82(Suppl 2A):6-28. [IDIS 227712] [PubMed 3548343]

123. Bounameux HM, Schifferli J, Montani JP et al. Renal failure associated with intravenous diphosphonates. Lancet. 1983; 1:471. [IDIS 166642] [PubMed 6131186]

124. Boyce BF, Fogelman I, Ralston S et al. Focal osteomalacia due to low-dose diphosphonate therapy in Paget’s disease. Lancet. 1984; 1:821-4. [IDIS 184178] [PubMed 6143140]

125. Procter & Gamble Pharmaceuticals. Didronel (etidronate disodium) tablets prescribing information. Cincinnati, OH; 2003 May.

126. Francis MD, Slough CL. Acute intravenous infusion of disodium dihydrogen (1-hydroxyethylidene)diphosphonate: mechanism of toxicity. J Pharm Sci. 1984; 73:1097-1100. [PubMed 6436463]

127. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414), to June 28, 1996. Rockville, MD; 1996 Jul.

128. Procter & Gamble Pharmaceuticals. Actonel(risedronate sodium) tablets prescribing information. Cincinnati, OH; 2000 Apr.

129. Miller PD, Brown JP, Siris ES et al. A randomized, double-blind comparison of risedronate and etidronate in the treatment of Paget’s disease of bone. Am J Med. 1999; 106:513-20. [IDIS 428270] [PubMed 10335722]

130. Plotkin LI, Weinstein RS, Parfitt AM et al. Prevention of osteocyte and osteoblast apoptosis by bisphosphonates and calcitonin. J Clin Invest. 1999; 104:1363-74. [PubMed 10562298]

131. Adachi JD, Bensen WG, Brown J et al. Intermittent etidronate therapy to prevent corticosteroid-induced osteoporosis. N Engl J Med. 1997; 337:382-7. [IDIS 389180] [PubMed 9241127]

132. Roux C, Oriente P, Laan R et al. Randomized trial of the effect of cyclical etidronate in the prevention of corticosteroid-induced bone loss. J Clin Endocrinol Metab. 1998; 83:1128-33. [IDIS 404610] [PubMed 9543129]

133. Adachi JD, Saag KG, Delmas PD et al. Two-year effects of alendronate on bone mineral density and vertebral fracture in patients receiving glucocorticoids: a randomized, double-blind, placebo-controlled extension trial. Arthritis Rheum. 2001; 44:202-11. [PubMed 11212161]

134. Reid DM, Hughes RA, Laan RF et al. Efficacy and safety of daily risedronate in the treatment of corticosteroid-induced osteoporosis in men and women: a randomized trial. J Bone Miner Res. 2000; 15:1006-20. [PubMed 10841169]

135. Diamond T, McGuigan L, Barbagallo S et al. Cyclical etidronate plus ergocalciferol prevents glucocorticoid-induced bone loss in postmenopausal women. Am J Med. 1995; 98:459-63. [IDIS 348269] [PubMed 7733124]

136. Cohen S, Levy RM, Keller M et al. Risedronate therapy prevents corticosteroid-induced bone loss: a twelve-month, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Arthritis Rheum. 1999; 42:2309-18. [IDIS 438381] [PubMed 10555025]

137. Wallach S, Cohen S, Reid DM et al. Effects of risedronate treatment on bone density and vertebral fracture in patients on corticosteroid therapy. Calcif Tissue Int. 2000; 67:277-85. [PubMed 11000340]

138. American College of Rheumatology Task Force on Osteoporosis Guidelines. Recommendations for the prevention and treatment of gluococorticoid-induced osteoporosis. Arthritis Rheum. 1996; 39:1791-801. [IDIS 375200] [PubMed 8912500]

139. American College of Rheumatology Ad Hoc Committee on Glucocorticoid-induced Osteoporosis. Recommendations for the prevention and treatment of gluococorticoid-induced osteoporosis: 2001 update. Arthritis Rheum. 2001; 44:1496-503. [IDIS 466759] [PubMed 11465699]

140. Sambrook PN. Corticosteroid osteoporosis: practical implications of recent trials. J Bone Miner Res. 2000; 15:1645-9. [PubMed 10976984]

141. Jenkins EA, Walker-Bone KE, Wood A et al. The prevention of corticosteroid-induced bone loss with intermittent cyclical etidronate. Scand J Rheumatol. 1999; 28:152-6. [PubMed 10380836]

142. Hanley DA, Ioannidis G, Adachi JD. Etridronate therapy in the treatment and prevention of osteoporosis. J Clin Densitom. 2000; 3:79-95. [PubMed 10745305]

143. Sebaldt RJ, Ioannidis G, Adachi JD et al. 36 month intermittent cyclical etidronate treatment in patients with established corticosteroid induced osteoporosis. J Rheumatol. 1999; 26:1545-9. [IDIS 429220] [PubMed 10405943]

144. Cortet B, Hachulla E, Barton I et al. Evaluation of the efficacy of etidronate therapy in preventing glucocorticoid-induced bone loss in patients with inflammatory rheumatic diseases. A randomized study. Rev Rhum Engl Ed. 1999; 66:214-9. [PubMed 10339777]

145. Pitt P, Li F, Todd P et al. A double blind placebo controlled study to determine the effects of intermittent cyclical etidronate on bone mineral density in patients on long-term oral corticosteroid treatment. Thorax. 1998; 53:351-6. [IDIS 410649] [PubMed 9708225]

146. Struys A, Snelder AA, Mulder H. Cyclical etidronate reverses bone loss of the spine and proximal femur in patients with established corticosteroid-induced osteoporosis. Am J Med. 1995; 99:235-42. [IDIS 353366] [PubMed 7653482]

147. Ruggiero SL, Mehrotra B, Rosenberg TJ et al. Osteonecrosis of the jaw associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg. 2004; 62:527-34. [IDIS 518769] [PubMed 15122554]

148. Novartis. Zometa (zoledronic acid) injection prescribing information. East Hanover, NJ; 2004 Aug.

149. Hohneker JA. Dear doctor letter regarding osteonecrosis of the jaw in patients with cancer receiving bisphophonates. East Hanover, NJ: Novartis; 2004 September 24.

150. Ruggiero SL, Mehrotra B. Ten years of alendronate treatment for osteoporosis in postmenopausal women. N Engl J Med. 2004; 351:191.

151. Bone HG, Santora AC. Ten years of alendronate treatment for osteoporosis in postmenopausal women. N Engl J Med. 2004; 351:191-2.

152. Food and Drug Administraiton. Center for Drug Evaluation and Research. Dugs@FDA:didronel. Available at . Accessed 2005 Jan 4.

a. North American Menopause Society. Management of osteoporosis in postmenopausal women: 2006 position statement of the North American Menopause Society. Menopause. 2006; 13:340-67. [PubMed 16735931]

b. Procter & Gamble Pharmaceuticals. Didronel (etidronate disodium) tablets prescribing information. Cincinnati, OH; 2005 May.

c. AHFS drug information 2007. McEvoy GK, ed. Etidronate. Bethesda, MD: American Society of Health-System Pharmacists; 2007:3703-7.

d. Merck. Fosamax (alendronate sodium) tablets and oral solution prescribing information. Whitehouse Station, NJ; 2006 Dec.

e. Sato Y, Kanoko T, Yasuda H et al. Beneficial effect of etidronate therapy in immobilized hip fracture patients. Am J Phys Med Rehabil. 2004; 83:298-303. [PubMed 15024332]

f. American College of Obstetricians and Gynecologists. Osteoporosis. Washington, DC; 2004 Jan. ACOG practice bulletin No. 50.

h. Kasting GB, Francis MD. Retention of etidronate in human, dog, and rat. J Bone Miner Res. 1992; 7:513-22. [PubMed 1615760]

i. Migliorati CA, Casiglia J, Epstein J et al. Managing the care of patients with bisphosphonate-associated osteonecrosis: an American Academy of Oral Medicine position paper. J Am Dent Assoc. 2005; 136:1656-68.

More Etidronate Disodium resources

• Etidronate Disodium Side Effects (in more detail)
• Etidronate Disodium Dosage
• Etidronate Disodium Use in Pregnancy & Breastfeeding
• Drug Images
• Etidronate Disodium Drug Interactions
• Etidronate Disodium Support Group
• 0 Reviews for Etidronate Disodium - Add your own review/rating

• Etidronate Prescribing Information (FDA)


• Didronel Prescribing Information (FDA)


• Didronel Advanced Consumer (Micromedex) - Includes Dosage Information


• Didronel MedFacts Consumer Leaflet (Wolters Kluwer)


• Didronel Consumer Overview

Compare Etidronate Disodium with other medications

• Heterotopic Ossification, Spinal Cord Injury
• Heterotopic Ossification, Total Hip Arthroplasty
• Hypercalcemia of Malignancy
• Osteoporosis
• Paget's Disease

Cafatine

Generic Name: caffeine and ergotamine (oral/rectal) (KAF een and er GOT a meen)

Brand Names: Cafergot, Migergot

What is caffeine and ergotamine?

Caffeine is a stimulant that causes narrowing of blood vessels (vasoconstriction).

Ergotamine is in a group of drugs called ergot alkaloids (ER-got AL-ka-loids). It works by narrowing the blood vessels around the brain. Ergotamine also affects blood flow patterns that are associated with certain types of headaches.

The combination of caffeine and ergotamine is used to treat or prevent a migraine type headache.

This medication will only treat a headache that has already begun. It will not prevent migraine headaches or reduce the number of attacks.

Caffeine and ergotamine should not be used to treat common tension headaches or any headache that seems to be different from your usual migraine headaches.

Caffeine and ergotamine may also be used for other purposes not listed in this medication guide.

What is the most important information I should know about caffeine and ergotamine?

This medication can harm an unborn baby or a nursing baby. Do not use caffeine and ergotamine if you are pregnant or breast-feeding. Do not use this medication if you are allergic to caffeine and ergotamine or other ergot medicines, or if you have a history of heart disease, angina (chest pain), blood circulation problems, history of a heart attack or stroke, coronary artery disease, uncontrolled high blood pressure, severe liver or kidney disease, or a serious infection. Using certain medications together with caffeine and ergotamine can cause even greater decreases in blood flow than caffeine and ergotamine used alone. A severe decrease in blood flow to the brain and other parts of the body can lead to dangerous side effects. Tell your doctor about all other medications you are using, especially antibiotics, antidepressants, heart or blood pressure medications, or medicines to treat HIV or AIDS.

Also tell your doctor about all of your medical conditions, especially breathing problems, high blood pressure, liver or kidney disease, or risk factors for coronary artery disease (diabetes, high blood pressure or cholesterol, menopause or hysterectomy, smoking, taking birth control pills, being overweight, having a family history of coronary artery disease, or being a man older than 40).

This medication will only treat a headache that has already begun. It will not prevent headaches or reduce the number of attacks.

Never use more than your prescribed dose of caffeine and ergotamine. Tell your doctor if the medicine seems to stop working as well in treating your migraine attacks. An overdose of caffeine and ergotamine can be fatal.

What should I discuss with my healthcare provider before using caffeine and ergotamine ?

Do not use this medication if you are allergic to caffeine or ergotamine, or other ergot medicine such as dihydroergotamine (D.H.E. 45, Migranal), ergonovine (Ergotrate), methylergonovine (Methergine), or methysergide (Sansert).

Do not use caffeine and ergotamine if you are pregnant or breast-feeding, or if you have:

• 
  

  a history of heart disease, angina (chest pain), blood circulation problems, or history of a heart attack or stroke;

  
  


• 
  

  coronary artery disease or "hardening of the arteries";

  
  


• 
  

  uncontrolled high blood pressure;

  
  


• severe liver disease;


• severe kidney disease; or


• 
  

  a serious infection called sepsis.

  
  

Using certain medications together with caffeine and ergotamine can cause even greater decreases in blood flow than caffeine and ergotamine used alone. A severe decrease in blood flow to the brain and other parts of the body can lead to dangerous side effects. Do not use caffeine and ergotamine if you are also using any of the following medications:

• 
  

  conivaptan (Vaprisol);

  
  


• 
  

  diclofenac (Arthrotec, Cataflam, Voltaren, Flector Patch, Solareze);

  
  


• 
  

  imatinib (Gleevec);

  
  


• 
  

  isoniazid (for treating tuberculosis);

  
  


• 
  

  an antibiotic such as clarithromycin (Biaxin), dalfopristin/quinupristin (Synercid), erythromycin (E.E.S., EryPed, Ery-Tab, Erythrocin), telithromycin (Ketek), or troleandomycin (Tao);

  
  


• 
  

  an antifungal medication such as clotrimazole (Mycelex Troche), itraconazole (Sporanox), ketoconazole (Nizoral), or voriconazole (Vfend);

  
  


• 
  

  an antidepressant such as nefazodone;

  
  


• 
  

  heart or blood pressure medication such as diltiazem (Cardizem, Dilacor, Tiazac), nicardipine (Cardene), quinidine (Quinaglute, Quinidex, Quin-Release), or verapamil (Calan, Covera, Isoptin, Verelan); or

  
  


• 
  

  HIV/AIDS medicine such as amprenavir (Agenerase), atazanavir (Reyataz), delavirdine (Rescriptor), fosamprenavir (Lexiva), indinavir (Crixivan), nelfinavir (Viracept), saquinavir (Invirase, Fortovase), or ritonavir (Norvir).

  
  

Caffeine and ergotamine can cause rare but serious side effects on the heart, including heart attack or stroke. If you have certain conditions, you may need a dose adjustment or special tests to safely use this medication. Before using caffeine and ergotamine, tell your doctor if you have:

• 
  

  breathing problems;

  
  


• 
  

  high blood pressure;

  
  


• 
  

  liver disease;

  
  


• 
  

  kidney disease; or

  
  


• 
  

  coronary artery disease (or risk factors that include diabetes, menopause, smoking, being overweight, having high blood pressure or high cholesterol, having a family history of coronary artery disease, being older than 40 and a man, or being a woman who has had a hysterectomy).

  
  

FDA pregnancy category X. This medication can cause birth defects. Do not use caffeine and ergotamine if you are pregnant. Tell your doctor right away if you become pregnant during treatment. Use an effective form of birth control while you are using caffeine and ergotamine. Caffeine and ergotamine passes into breast milk and may be harmful to a nursing infant. Do not use caffeine and ergotamine without telling your doctor if you are breast-feeding a baby.

How should I use caffeine and ergotamine?

Use this medication exactly as prescribed by your doctor. Never use more than your prescribed dose of caffeine and ergotamine. Follow the directions on your prescription label. Tell your doctor if the medicine seems to stop working as well in treating your migraine attacks. Caffeine and ergotamine is not for daily use.

To use caffeine and ergotamine tablets: Take 2 tablets of caffeine and ergotamine as soon as you notice headache symptoms, or after an attack has already begun.

If your headache does not completely go away, you may take 1 more tablet after at least 30 minutes have passed. If additional medication is needed, you may take 1 tablet every 30 minutes up to a total of 6 tablets for one migraine attack.

If you still have migraine symptoms after taking a total of 6 tablets, call your doctor. Do not take more than a total of 6 tablets in any 24-hour period. Do not take more than a total of 10 tablets over a period of 7 days.

To use caffeine and ergotamine rectal suppositories: Insert 1 suppository at the first sign of migraine headache symptoms, or after an attack has already begun. If your headache does not completely go away, use 1 more suppository after at least 1 hour has passed.

Do not take a rectal suppository by mouth. It is for use only in your rectum.

Try to empty your bladder just before using the suppository. Remove the outer wrapper from the suppository and insert it gently into the rectum, pointed tip first. Avoid handling the suppository too long or it will melt in your hands.

For best results, lie down after inserting the suppository and hold it in for a few minutes. The suppository will melt quickly once inserted and you should feel little or no discomfort while holding it in. Avoid using the bathroom just after you have inserted the suppository.

If you still have migraine symptoms after using a total of 2 rectal suppositories, call your doctor. Do not use more than a total of 2 suppositories per headache. Do not use more than a total of 5 suppositories over a period of 7 days. Do not give this medication to anyone else, even if they have the same headache symptoms you have. Caffeine and ergotamine can be dangerous if it is used to treat headache in a person who has not been diagnosed by a doctor as having true migraine headaches. Store caffeine and ergotamine at room temperature away from moisture, heat, and light. Do not use any stored caffeine and ergotamine if the expiration date on the label has passed.

What happens if I miss a dose?

Since caffeine and ergotamine is used only when needed, you are not likely to miss a dose.

Do not take more than 6 caffeine and ergotamine tablets per day or more than 10 tablets per week. Do not use more than 2 suppositories per headache or 5 suppositories per week.

What happens if I overdose?

Seek emergency medical attention if you think you have used too much of this medicine. An overdose of caffeine and ergotamine can be fatal.

Overdose can cause vomiting, confusion, drowsiness, weak pulses in your arms and legs, numbness and tingling or pain in your hands or feet, blue-colored fingers or toes, fainting, and seizure (convulsions).

What should I avoid while using caffeine and ergotamine?

Do not use caffeine and ergotamine within 24 hours before or after using another migraine headache medicine, including:

• 
  

  dihydroergotamine (D.H.E. 45, Migranal), caffeine and ergotamine (Cafergot, Ercaf, Wigraine), ergonovine (Ergotrate), methylergonovine (Methergine), methysergide (Sansert); or

  
  


• 
  

  almotriptan (Axert), eletriptan (Relpax), frovatriptan (Frova), naratriptan (Amerge), sumatriptan (Imitrex), rizatriptan (Maxalt, Maxalt-MLT), or zolmitriptan (Zomig).

  
  

Grapefruit and grapefruit juice may interact with caffeine and ergotamine and lead to potentially dangerous effects. Discuss the use of grapefruit products with your doctor. Do not increase or decrease the amount of grapefruit products in your diet without first talking to your doctor.

Caffeine and ergotamine side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop using caffeine and ergotamine and call your doctor at once if you have a serious side effect such as:

• 
  

  sudden numbness or weakness, especially on one side of the body;

  
  


• 
  

  sudden headache, confusion, problems with vision, speech, or balance;

  
  


• 
  

  fast or slow heart rate;

  
  


• 
  

  muscle pain in your arms or legs;

  
  


• 
  

  leg weakness;

  
  


• 
  

  numbness or tingling and a pale or blue-colored appearance in your fingers or toes;

  
  


• 
  

  severe pain in your stomach or lower back;

  
  


• 
  

  urinating less than usual or not at all;

  
  


• 
  

  painful sores on your rectum after using the rectal suppositories;

  
  


• 
  

  swelling or itching in any part of your body;

  
  


• 
  

  cough with stabbing chest pain and trouble breathing; or

  
  


• 
  

  dangerously high blood pressure (severe headache, blurred vision, buzzing in your ears, anxiety, confusion, chest pain, shortness of breath, uneven heartbeats, seizure).

  
  

Less serious side effects may include:

• 
  

  dizziness, spinning sensation;

  
  


• 
  

  weakness;

  
  


• 
  

  nausea, vomiting; or

  
  


• 
  

  mild itching.

  
  

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.

What other drugs will affect caffeine and ergotamine?

Many drugs can interact with caffeine and ergotamine. Below is just a partial list. Talk with your doctor before using caffeine and ergotamine if you are also taking:

• 
  

  birth control pills;

  
  


• 
  

  zileuton (Zyflo);

  
  


• 
  

  cold or allergy medications;

  
  


• 
  

  nicotine (Nicoderm, Nicorette);

  
  


• 
  

  diet pills, stimulants, or medication to treat ADHD (such as Ritalin or Adderall);

  
  


• 
  

  an antidepressant such fluoxetine (Prozac, Sarafem), fluvoxamine (Luvox), nefazodone (Serzone), paroxetine (Paxil), sertraline (Zoloft), and others;

  
  


• 
  

  nitroglycerin or other nitrate medicines such as isosorbide (Isordil, Dilatrate, Imdur, Monoket); or

  
  


• 
  

  heart or blood pressure medication such as atenolol (Tenormin), carvedilol (Coreg), labetalol (Normodyne, Trandate), metoprolol (Lopressor, Toprol), nadolol (Corgard), propranolol (Inderal, InnoPran), sotalol (Betapace), and others.

  
  

This list is not complete and there may be other drugs that can interact with caffeine and ergotamine. Tell your doctor about all your prescription and over-the-counter medications, vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start a new medication without telling your doctor.

More Cafatine resources

• Cafatine Side Effects (in more detail)
• Cafatine Use in Pregnancy & Breastfeeding
• Cafatine Drug Interactions
• Cafatine Support Group
• 0 Reviews for Cafatine - Add your own review/rating

• Cafergot Advanced Consumer (Micromedex) - Includes Dosage Information


• Cafergot MedFacts Consumer Leaflet (Wolters Kluwer)


• Cafergot Prescribing Information (FDA)


• Migergot Suppositories MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Cafatine with other medications

• Cluster Headaches
• Migraine

Where can I get more information?

• Your pharmacist can provide more information about caffeine and ergotamine.

See also: Cafatine side effects (in more detail)

Neurontin

Generic Name: gabapentin

Dosage Form: capsules, tablets, oral solution
Neurontin® (gabapentin) Capsules

Neurontin® (gabapentin) Tablets

Neurontin®(gabapentin) Oral Solution

Neurontin Description

Neurontin® (gabapentin) Capsules, Neurontin® (gabapentin) Tablets, and Neurontin® (gabapentin) Oral Solution are supplied as imprinted hard shell capsules containing 100 mg, 300 mg, and 400 mg of gabapentin, elliptical film-coated tablets containing 600 mg and 800 mg of gabapentin or an oral solution containing 250 mg/5 mL of gabapentin.

The inactive ingredients for the capsules are lactose, cornstarch, and talc. The 100 mg capsule shell contains gelatin and titanium dioxide. The 300 mg capsule shell contains gelatin, titanium dioxide, and yellow iron oxide. The 400 mg capsule shell contains gelatin, red iron oxide, titanium dioxide, and yellow iron oxide. The imprinting ink contains FD&C Blue No. 2 and titanium dioxide.

The inactive ingredients for the tablets are poloxamer 407, copolyvidonum, cornstarch, magnesium stearate, hydroxypropyl cellulose, talc, candelilla wax, and purified water.

The inactive ingredients for the oral solution are glycerin, xylitol, purified water, and artificial cool strawberry anise flavor.

Gabapentin is described as 1-(aminomethyl)cyclohexaneacetic acid with a molecular formula of C9H17NO2 and a molecular weight of 171.24. The structural formula of gabapentin is:

Gabapentin is a white to off-white crystalline solid with a pKa1 of 3.7 and a pKa2 of 10.7. It is freely soluble in water and both basic and acidic aqueous solutions. The log of the partition coefficient (n-octanol/0.05M phosphate buffer) at pH 7.4 is –1.25.

Neurontin - Clinical Pharmacology

Mechanism of Action

The mechanism by which gabapentin exerts its analgesic action is unknown, but in animal models of analgesia, gabapentin prevents allodynia (pain-related behavior in response to a normally innocuous stimulus) and hyperalgesia (exaggerated response to painful stimuli). In particular, gabapentin prevents pain-related responses in several models of neuropathic pain in rats or mice (e.g., spinal nerve ligation models, streptozocin-induced diabetes model, spinal cord injury model, acute herpes zoster infection model). Gabapentin also decreases pain-related responses after peripheral inflammation (carrageenan footpad test, late phase of formalin test). Gabapentin did not alter immediate pain-related behaviors (rat tail flick test, formalin footpad acute phase, acetic acid abdominal constriction test, footpad heat irradiation test). The relevance of these models to human pain is not known.

The mechanism by which gabapentin exerts its anticonvulsant action is unknown, but in animal test systems designed to detect anticonvulsant activity, gabapentin prevents seizures as do other marketed anticonvulsants. Gabapentin exhibits antiseizure activity in mice and rats in both the maximal electroshock and pentylenetetrazole seizure models and other preclinical models (e.g., strains with genetic epilepsy, etc.). The relevance of these models to human epilepsy is not known.

Gabapentin is structurally related to the neurotransmitter GABA (gamma-aminobutyric acid) but it does not modify GABAA or GABAB radioligand binding, it is not converted metabolically into GABA or a GABA agonist, and it is not an inhibitor of GABA uptake or degradation. Gabapentin was tested in radioligand binding assays at concentrations up to 100 µM and did not exhibit affinity for a number of other common receptor sites, including benzodiazepine, glutamate, N-methyl-D-aspartate (NMDA), quisqualate, kainate, strychnine-insensitive or strychnine-sensitive glycine, alpha 1, alpha 2, or beta adrenergic, adenosine A1 or A2, cholinergic muscarinic or nicotinic, dopamine D1 or D2, histamine H1, serotonin S1 or S2, opiate mu, delta or kappa, cannabinoid 1, voltage-sensitive calcium channel sites labeled with nitrendipine or diltiazem, or at voltage-sensitive sodium channel sites labeled with batrachotoxinin A 20-alpha-benzoate. Furthermore, gabapentin did not alter the cellular uptake of dopamine, noradrenaline, or serotonin.

In vitro studies with radiolabeled gabapentin have revealed a gabapentin binding site in areas of rat brain including neocortex and hippocampus. A high-affinity binding protein in animal brain tissue has been identified as an auxiliary subunit of voltage-activated calcium channels. However, functional correlates of gabapentin binding, if any, remain to be elucidated.

Pharmacokinetics and Drug Metabolism

All pharmacological actions following gabapentin administration are due to the activity of the parent compound; gabapentin is not appreciably metabolized in humans.

Oral Bioavailability

Gabapentin bioavailability is not dose proportional; i.e., as dose is increased, bioavailability decreases. Bioavailability of gabapentin is approximately 60%, 47%, 34%, 33%, and 27% following 900, 1200, 2400, 3600, and 4800 mg/day given in 3 divided doses, respectively. Food has only a slight effect on the rate and extent of absorption of gabapentin (14% increase in AUC and Cmax).

Distribution

Less than 3% of gabapentin circulates bound to plasma protein. The apparent volume of distribution of gabapentin after 150 mg intravenous administration is 58±6 L (mean ±SD). In patients with epilepsy, steady-state predose (Cmin) concentrations of gabapentin in cerebrospinal fluid were approximately 20% of the corresponding plasma concentrations.

Elimination

Gabapentin is eliminated from the systemic circulation by renal excretion as unchanged drug. Gabapentin is not appreciably metabolized in humans.

Gabapentin elimination half-life is 5 to 7 hours and is unaltered by dose or following multiple dosing. Gabapentin elimination rate constant, plasma clearance, and renal clearance are directly proportional to creatinine clearance (see CLINICAL PHARMACOLOGY, Special Populations: Adult Patients With Renal Insufficiency, below). In elderly patients, and in patients with impaired renal function, gabapentin plasma clearance is reduced. Gabapentin can be removed from plasma by hemodialysis.

Dosage adjustment in patients with compromised renal function or undergoing hemodialysis is recommended (see DOSAGE AND ADMINISTRATION, Table 6).

Special Populations

Adult Patients With Renal Insufficiency

Subjects (N=60) with renal insufficiency (mean creatinine clearance ranging from 13–114 mL/min) were administered single 400 mg oral doses of gabapentin. The mean gabapentin half-life ranged from about 6.5 hours (patients with creatinine clearance >60 mL/min) to 52 hours (creatinine clearance <30 mL/min) and gabapentin renal clearance from about 90 mL/min (>60 mL/min group) to about 10 mL/min (<30 mL/min). Mean plasma clearance (CL/F) decreased from approximately 190 mL/min to 20 mL/min.

Dosage adjustment in adult patients with compromised renal function is necessary (see DOSAGE AND ADMINISTRATION). Pediatric patients with renal insufficiency have not been studied.

Hemodialysis

In a study in anuric adult subjects (N=11), the apparent elimination half-life of gabapentin on nondialysis days was about 132 hours; during dialysis the apparent half-life of gabapentin was reduced to 3.8 hours. Hemodialysis thus has a significant effect on gabapentin elimination in anuric subjects.

Dosage adjustment in patients undergoing hemodialysis is necessary (see DOSAGE AND ADMINISTRATION).

Hepatic Disease

Because gabapentin is not metabolized, no study was performed in patients with hepatic impairment.

Age

The effect of age was studied in subjects 20–80 years of age. Apparent oral clearance (CL/F) of gabapentin decreased as age increased, from about 225 mL/min in those under 30 years of age to about 125 mL/min in those over 70 years of age. Renal clearance (CLr) and CLr adjusted for body surface area also declined with age; however, the decline in the renal clearance of gabapentin with age can largely be explained by the decline in renal function. Reduction of gabapentin dose may be required in patients who have age related compromised renal function. (See PRECAUTIONS, Geriatric Use, and DOSAGE AND ADMINISTRATION.)

Pediatric

Gabapentin pharmacokinetics were determined in 48 pediatric subjects between the ages of 1 month and 12 years following a dose of approximately 10 mg/kg. Peak plasma concentrations were similar across the entire age group and occurred 2 to 3 hours postdose. In general, pediatric subjects between 1 month and <5 years of age achieved approximately 30% lower exposure (AUC) than that observed in those 5 years of age and older. Accordingly, oral clearance normalized per body weight was higher in the younger children. Apparent oral clearance of gabapentin was directly proportional to creatinine clearance. Gabapentin elimination half-life averaged 4.7 hours and was similar across the age groups studied.

A population pharmacokinetic analysis was performed in 253 pediatric subjects between 1 month and 13 years of age. Patients received 10 to 65 mg/kg/day given TID. Apparent oral clearance (CL/F) was directly proportional to creatinine clearance and this relationship was similar following a single dose and at steady state. Higher oral clearance values were observed in children <5 years of age compared to those observed in children 5 years of age and older, when normalized per body weight. The clearance was highly variable in infants <1 year of age. The normalized CL/F values observed in pediatric patients 5 years of age and older were consistent with values observed in adults after a single dose. The oral volume of distribution normalized per body weight was constant across the age range.

These pharmacokinetic data indicate that the effective daily dose in pediatric patients with epilepsy ages 3 and 4 years should be 40 mg/kg/day to achieve average plasma concentrations similar to those achieved in patients 5 years of age and older receiving gabapentin at 30 mg/kg/day (see DOSAGE AND ADMINISTRATION).

Gender

Although no formal study has been conducted to compare the pharmacokinetics of gabapentin in men and women, it appears that the pharmacokinetic parameters for males and females are similar and there are no significant gender differences.

Race

Pharmacokinetic differences due to race have not been studied. Because gabapentin is primarily renally excreted and there are no important racial differences in creatinine clearance, pharmacokinetic differences due to race are not expected.

Clinical Studies

Postherpetic Neuralgia

Neurontin was evaluated for the management of postherpetic neuralgia (PHN) in 2 randomized, double-blind, placebo-controlled, multicenter studies; N=563 patients in the intent-to-treat (ITT) population (Table 1). Patients were enrolled if they continued to have pain for more than 3 months after healing of the herpes zoster skin rash.

TABLE 1. Controlled PHN Studies: Duration, Dosages, and Number of Patients

Study	Study Duration	Gabapentin (mg/day)* Target Dose	Patients Receiving Gabapentin	Patients Receiving Placebo
* Given in 3 divided doses (TID)
1	8 weeks	3600	113	116
2	7 weeks	1800, 2400	223	111
Total			336	227

Each study included a 1-week baseline during which patients were screened for eligibility and a 7- or 8-week double-blind phase (3 or 4 weeks of titration and 4 weeks of fixed dose). Patients initiated treatment with titration to a maximum of 900 mg/day gabapentin over 3 days. Dosages were then to be titrated in 600 to 1200 mg/day increments at 3- to 7-day intervals to target dose over 3 to 4 weeks. In Study 1, patients were continued on lower doses if not able to achieve the target dose. During baseline and treatment, patients recorded their pain in a daily diary using an 11-point numeric pain rating scale ranging from 0 (no pain) to 10 (worst possible pain). A mean pain score during baseline of at least 4 was required for randomization (baseline mean pain score for Studies 1 and 2 combined was 6.4). Analyses were conducted using the ITT population (all randomized patients who received at least one dose of study medication).

Both studies showed significant differences from placebo at all doses tested.

A significant reduction in weekly mean pain scores was seen by Week 1 in both studies, and significant differences were maintained to the end of treatment. Comparable treatment effects were observed in all active treatment arms. Pharmacokinetic/pharmacodynamic modeling provided confirmatory evidence of efficacy across all doses. Figures 1 and 2 show these changes for Studies 1 and 2.

Figure 1. Weekly Mean Pain Scores (Observed Cases in ITT Population): Study 1

Figure 2. Weekly Mean Pain Scores (Observed Cases in ITT Population): Study 2

The proportion of responders (those patients reporting at least 50% improvement in endpoint pain score compared with baseline) was calculated for each study (Figure 3).

Figure 3. Proportion of Responders (patients with ≥50% reduction in pain score) at Endpoint: Controlled PHN Studies

Epilepsy

The effectiveness of Neurontin as adjunctive therapy (added to other antiepileptic drugs) was established in multicenter placebo-controlled, double-blind, parallel-group clinical trials in adult and pediatric patients (3 years and older) with refractory partial seizures.

Evidence of effectiveness was obtained in three trials conducted in 705 patients (age 12 years and above) and one trial conducted in 247 pediatric patients (3 to 12 years of age). The patients enrolled had a history of at least 4 partial seizures per month in spite of receiving one or more antiepileptic drugs at therapeutic levels and were observed on their established antiepileptic drug regimen during a 12-week baseline period (6 weeks in the study of pediatric patients). In patients continuing to have at least 2 (or 4 in some studies) seizures per month, Neurontin or placebo was then added on to the existing therapy during a 12-week treatment period. Effectiveness was assessed primarily on the basis of the percent of patients with a 50% or greater reduction in seizure frequency from baseline to treatment (the "responder rate") and a derived measure called response ratio, a measure of change defined as (T – B)/(T + B), in which B is the patient's baseline seizure frequency and T is the patient's seizure frequency during treatment. Response ratio is distributed within the range –1 to +1. A zero value indicates no change while complete elimination of seizures would give a value of –1; increased seizure rates would give positive values. A response ratio of –0.33 corresponds to a 50% reduction in seizure frequency. The results given below are for all partial seizures in the intent-to-treat (all patients who received any doses of treatment) population in each study, unless otherwise indicated.

One study compared Neurontin 1200 mg/day divided TID with placebo. Responder rate was 23% (14/61) in the Neurontin group and 9% (6/66) in the placebo group; the difference between groups was statistically significant. Response ratio was also better in the Neurontin group (–0.199) than in the placebo group (–0.044), a difference that also achieved statistical significance.

A second study compared primarily 1200 mg/day divided TID Neurontin (N=101) with placebo (N=98). Additional smaller Neurontin dosage groups (600 mg/day, N=53; 1800 mg/day, N=54) were also studied for information regarding dose response. Responder rate was higher in the Neurontin 1200 mg/day group (16%) than in the placebo group (8%), but the difference was not statistically significant. The responder rate at 600 mg (17%) was also not significantly higher than in the placebo, but the responder rate in the 1800 mg group (26%) was statistically significantly superior to the placebo rate. Response ratio was better in the Neurontin 1200 mg/day group (–0.103) than in the placebo group (–0.022); but this difference was also not statistically significant (p = 0.224). A better response was seen in the Neurontin 600 mg/day group (–0.105) and 1800 mg/day group (–0.222) than in the 1200 mg/day group, with the 1800 mg/day group achieving statistical significance compared to the placebo group.

A third study compared Neurontin 900 mg/day divided TID (N=111) and placebo (N=109). An additional Neurontin 1200 mg/day dosage group (N=52) provided dose-response data. A statistically significant difference in responder rate was seen in the Neurontin 900 mg/day group (22%) compared to that in the placebo group (10%). Response ratio was also statistically significantly superior in the Neurontin 900 mg/day group (–0.119) compared to that in the placebo group (–0.027), as was response ratio in 1200 mg/day Neurontin (–0.184) compared to placebo.

Analyses were also performed in each study to examine the effect of Neurontin on preventing secondarily generalized tonic-clonic seizures. Patients who experienced a secondarily generalized tonic-clonic seizure in either the baseline or in the treatment period in all three placebo-controlled studies were included in these analyses. There were several response ratio comparisons that showed a statistically significant advantage for Neurontin compared to placebo and favorable trends for almost all comparisons.

Analysis of responder rate using combined data from all three studies and all doses (N=162, Neurontin; N=89, placebo) also showed a significant advantage for Neurontin over placebo in reducing the frequency of secondarily generalized tonic-clonic seizures.

In two of the three controlled studies, more than one dose of Neurontin was used. Within each study, the results did not show a consistently increased response to dose. However, looking across studies, a trend toward increasing efficacy with increasing dose is evident (see Figure 4).

Figure 4. Responder Rate in Patients Receiving Neurontin Expressed as a Difference from Placebo by Dose and Study: Adjunctive Therapy Studies in Patients ≥12 Years of Age with Partial Seizures

In the figure, treatment effect magnitude, measured on the Y axis in terms of the difference in the proportion of gabapentin and placebo-assigned patients attaining a 50% or greater reduction in seizure frequency from baseline, is plotted against the daily dose of gabapentin administered (X axis).

Although no formal analysis by gender has been performed, estimates of response (Response Ratio) derived from clinical trials (398 men, 307 women) indicate no important gender differences exist. There was no consistent pattern indicating that age had any effect on the response to Neurontin. There were insufficient numbers of patients of races other than Caucasian to permit a comparison of efficacy among racial groups.

A fourth study in pediatric patients age 3 to 12 years compared 25 – 35 mg/kg/day Neurontin (N=118) with placebo (N=127). For all partial seizures in the intent-to-treat population, the response ratio was statistically significantly better for the Neurontin group (–0.146) than for the placebo group (–0.079). For the same population, the responder rate for Neurontin (21%) was not significantly different from placebo (18%).

A study in pediatric patients age 1 month to 3 years compared 40 mg/kg/day Neurontin (N=38) with placebo (N=38) in patients who were receiving at least one marketed antiepileptic drug and had at least one partial seizure during the screening period (within 2 weeks prior to baseline). Patients had up to 48 hours of baseline and up to 72 hours of double-blind video EEG monitoring to record and count the occurrence of seizures. There were no statistically significant differences between treatments in either the response ratio or responder rate.

Indications and Usage for Neurontin

Postherpetic Neuralgia

Neurontin (gabapentin) is indicated for the management of postherpetic neuralgia in adults.

Epilepsy

Neurontin (gabapentin) is indicated as adjunctive therapy in the treatment of partial seizures with and without secondary generalization in patients over 12 years of age with epilepsy. Neurontin is also indicated as adjunctive therapy in the treatment of partial seizures in pediatric patients age 3 – 12 years.

Contraindications

Neurontin is contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients.

Warnings

Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including Neurontin, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5–100 years) in the clinical trials analyzed.

Table 2 shows absolute and relative risk by indication for all evaluated AEDs.

Table 2 Risk by indication for antiepileptic drugs in the pooled analysis

Indication	Placebo Patients with Events Per 1000 Patients	Drug Patients with Events Per 1000 Patients	Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients	Risk Difference: Additional Drug Patients with Events Per 1000 Patients
Epilepsy	1.0	3.4	3.5	2.4
Psychiatric	5.7	8.5	1.5	2.9
Other	1.0	1.8	1.9	0.9
Total	2.4	4.3	1.8	1.9

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing Neurontin or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

Neuropsychiatric Adverse Events-Pediatric Patients 3–12 years of age

Gabapentin use in pediatric patients with epilepsy 3–12 years of age is associated with the occurrence of central nervous system related adverse events. The most significant of these can be classified into the following categories: 1) emotional lability (primarily behavioral problems), 2) hostility, including aggressive behaviors, 3) thought disorder, including concentration problems and change in school performance, and 4) hyperkinesia (primarily restlessness and hyperactivity). Among the gabapentin-treated patients, most of the events were mild to moderate in intensity.

In controlled trials in pediatric patients 3–12 years of age, the incidence of these adverse events was: emotional lability 6% (gabapentin-treated patients) vs. 1.3% (placebo-treated patients); hostility 5.2% vs. 1.3%; hyperkinesia 4.7% vs. 2.9%; and thought disorder 1.7% vs. 0%. One of these events, a report of hostility, was considered serious. Discontinuation of gabapentin treatment occurred in 1.3% of patients reporting emotional lability and hyperkinesia and 0.9% of gabapentin-treated patients reporting hostility and thought disorder. One placebo-treated patient (0.4%) withdrew due to emotional lability.

Withdrawal Precipitated Seizure, Status Epilepticus

Antiepileptic drugs should not be abruptly discontinued because of the possibility of increasing seizure frequency.

In the placebo-controlled studies in patients >12 years of age, the incidence of status epilepticus in patients receiving Neurontin was 0.6% (3 of 543) vs. 0.5% in patients receiving placebo (2 of 378). Among the 2074 patients >12 years of age treated with Neurontin across all studies (controlled and uncontrolled), 31 (1.5%) had status epilepticus. Of these, 14 patients had no prior history of status epilepticus either before treatment or while on other medications. Because adequate historical data are not available, it is impossible to say whether or not treatment with Neurontin is associated with a higher or lower rate of status epilepticus than would be expected to occur in a similar population not treated with Neurontin.

Tumorigenic Potential

In standard preclinical in vivo lifetime carcinogenicity studies, an unexpectedly high incidence of pancreatic acinar adenocarcinomas was identified in male, but not female, rats. (See PRECAUTIONS, Carcinogenesis, Mutagenesis, Impairment of Fertility.) The clinical significance of this finding is unknown. Clinical experience during gabapentin's premarketing development provides no direct means to assess its potential for inducing tumors in humans.

In clinical studies in adjunctive therapy in epilepsy comprising 2085 patient-years of exposure in patients >12 years of age, new tumors were reported in 10 patients (2 breast, 3 brain, 2 lung, 1 adrenal, 1 non-Hodgkin's lymphoma, 1 endometrial carcinoma in situ), and preexisting tumors worsened in 11 patients (9 brain, 1 breast, 1 prostate) during or up to 2 years following discontinuation of Neurontin. Without knowledge of the background incidence and recurrence in a similar population not treated with Neurontin, it is impossible to know whether the incidence seen in this cohort is or is not affected by treatment.

Sudden and Unexplained Death in Patients With Epilepsy

During the course of premarketing development of Neurontin, 8 sudden and unexplained deaths were recorded among a cohort of 2203 patients treated (2103 patient-years of exposure).

Some of these could represent seizure-related deaths in which the seizure was not observed, e.g., at night. This represents an incidence of 0.0038 deaths per patient-year. Although this rate exceeds that expected in a healthy population matched for age and sex, it is within the range of estimates for the incidence of sudden unexplained deaths in patients with epilepsy not receiving Neurontin (ranging from 0.0005 for the general population of epileptics to 0.003 for a clinical trial population similar to that in the Neurontin program, to 0.005 for patients with refractory epilepsy). Consequently, whether these figures are reassuring or raise further concern depends on comparability of the populations reported upon to the Neurontin cohort and the accuracy of the estimates provided.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including Neurontin. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved.

It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Neurontin should be discontinued if an alternative etiology for the signs or symptoms cannot be established.

Precautions

Information for Patients

Inform patients of the availability of a Medication Guide, and instruct them to read the Medication Guide prior to taking Neurontin. Instruct patients to take Neurontin only as prescribed.

Patients, their caregivers, and families should be counseled that AEDs, including Neurontin, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

Patients should be advised that Neurontin may cause dizziness, somnolence, and other symptoms and signs of CNS depression. Accordingly, they should be advised neither to drive a car nor to operate other complex machinery until they have gained sufficient experience on Neurontin to gauge whether or not it affects their mental and/or motor performance adversely.

Patients who require concomitant treatment with morphine may experience increases in gabapentin concentrations. Patients should be carefully observed for signs of CNS depression, such as somnolence, and the dose of Neurontin or morphine should be reduced appropriately (see PRECAUTIONS, Drug Interactions).

Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 (see PRECAUTIONS, Pregnancy).

Prior to initiation of treatment with Neurontin, the patient should be instructed that a rash or other signs or symtoms of hypersensitivity (such as fever or lymphadenopathy) may herald a serious medical event and that the patient should report any such occurrence to a physician immediately.

Laboratory Tests

Clinical trials data do not indicate that routine monitoring of clinical laboratory parameters is necessary for the safe use of Neurontin. The value of monitoring gabapentin blood concentrations has not been established. Neurontin may be used in combination with other antiepileptic drugs without concern for alteration of the blood concentrations of gabapentin or of other antiepileptic drugs.

Drug Interactions

In vitro studies were conducted to investigate the potential of gabapentin to inhibit the major cytochrome P450 enzymes (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4) that mediate drug and xenobiotic metabolism using isoform selective marker substrates and human liver microsomal preparations. Only at the highest concentration tested (171 µg/mL; 1 mM) was a slight degree of inhibition (14%–30%) of isoform CYP2A6 observed. No inhibition of any of the other isoforms tested was observed at gabapentin concentrations up to 171 µg/mL (approximately 15 times the Cmax at 3600 mg/day).

Gabapentin is not appreciably metabolized nor does it interfere with the metabolism of commonly coadministered antiepileptic drugs.

The drug interaction data described in this section were obtained from studies involving healthy adults and adult patients with epilepsy.

Phenytoin

In a single (400 mg) and multiple dose (400 mg TID) study of Neurontin in epileptic patients (N=8) maintained on phenytoin monotherapy for at least 2 months, gabapentin had no effect on the steady-state trough plasma concentrations of phenytoin and phenytoin had no effect on gabapentin pharmacokinetics.

Carbamazepine

Steady-state trough plasma carbamazepine and carbamazepine 10, 11 epoxide concentrations were not affected by concomitant gabapentin (400 mg TID; N=12) administration. Likewise, gabapentin pharmacokinetics were unaltered by carbamazepine administration.

Valproic Acid

The mean steady-state trough serum valproic acid concentrations prior to and during concomitant gabapentin administration (400 mg TID; N=17) were not different and neither were gabapentin pharmacokinetic parameters affected by valproic acid.

Phenobarbital

Estimates of steady-state pharmacokinetic parameters for phenobarbital or gabapentin (300 mg TID; N=12) are identical whether the drugs are administered alone or together.

Naproxen

Coadministration (N=18) of naproxen sodium capsules (250 mg) with Neurontin (125 mg) appears to increase the amount of gabapentin absorbed by 12% to 15%. Gabapentin had no effect on naproxen pharmacokinetic parameters. These doses are lower than the therapeutic doses for both drugs. The magnitude of interaction within the recommended dose ranges of either drug is not known.

Hydrocodone

Coadministration of Neurontin (125 to 500 mg; N=48) decreases hydrocodone (10 mg; N=50) Cmax and AUC values in a dose-dependent manner relative to administration of hydrocodone alone; Cmax and AUC values are 3% to 4% lower, respectively, after administration of 125 mg Neurontin and 21% to 22% lower, respectively, after administration of 500 mg Neurontin. The mechanism for this interaction is unknown. Hydrocodone increases gabapentin AUC values by 14%. The magnitude of interaction at other doses is not known.

Morphine

A literature article reported that when a 60 mg controlled-release morphine capsule was administered 2 hours prior to a 600 mg Neurontin capsule (N=12), mean gabapentin AUC increased by 44% compared to gabapentin administered without morphine (see PRECAUTIONS). Morphine pharmacokinetic parameter values were not affected by administration of Neurontin 2 hours after morphine. The magnitude of interaction at other doses is not known.

Cimetidine

In the presence of cimetidine at 300 mg QID (N=12), the mean apparent oral clearance of gabapentin fell by 14% and creatinine clearance fell by 10%. Thus, cimetidine appeared to alter the renal excretion of both gabapentin and creatinine, an endogenous marker of renal function. This small decrease in excretion of gabapentin by cimetidine is not expected to be of clinical importance. The effect of gabapentin on cimetidine was not evaluated.

Oral Contraceptive

Based on AUC and half-life, multiple-dose pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of tablets containing 2.5 mg of norethindrone acetate and 50 mcg of ethinyl estradiol were similar with and without coadministration of gabapentin (400 mg TID; N=13). The Cmax of norethindrone was 13% higher when it was coadministered with gabapentin; this interaction is not expected to be of clinical importance.

Antacid (Maalox®)

Maalox reduced the bioavailability of gabapentin (N=16) by about 20%. This decrease in bioavailability was about 5% when gabapentin was administered 2 hours after Maalox. It is recommended that gabapentin be taken at least 2 hours following Maalox administration.

Effect of Probenecid

Probenecid is a blocker of renal tubular secretion. Gabapentin pharmacokinetic parameters without and with probenecid were comparable. This indicates that gabapentin does not undergo renal tubular secretion by the pathway that is blocked by probenecid.

Drug/Laboratory Test Interactions

Because false positive readings were reported with the Ames N-Multistix SG® dipstick test for urinary protein when gabapentin was added to other antiepileptic drugs, the more specific sulfosalicylic acid precipitation procedure is recommended to determine the presence of urine protein.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Gabapentin was given in the diet to mice at 200, 600, and 2000 mg/kg/day and to rats at 250, 1000, and 2000 mg/kg/day for 2 years. A statistically significant increase in the incidence of pancreatic acinar cell adenomas and carcinomas was found in male rats receiving the high dose; the no-effect dose for the occurrence of carcinomas was 1000 mg/kg/day. Peak plasma concentrations of gabapentin in rats receiving the high dose of 2000 mg/kg were 10 times higher than plasma concentrations in humans receiving 3600 mg per day, and in rats receiving 1000 mg/kg/day, peak plasma concentrations were 6.5 times higher than in humans receiving 3600 mg/day. The pancreatic acinar cell carcinomas did not affect survival, did not metastasize, and were not locally invasive. The relevance of this finding to carcinogenic risk in humans is unclear.

Studies designed to investigate the mechanism of gabapentin-induced pancreatic carcinogenesis in rats indicate that gabapentin stimulates DNA synthesis in rat pancreatic acinar cells in vitro and, thus, may be acting as a tumor promoter by enhancing mitogenic activity. It is not known whether gabapentin has the ability to increase cell proliferation in other cell types or in other species, including humans.

Gabapentin did not demonstrate mutagenic or genotoxic potential in three in vitro and four in vivo assays. It was negative in the Ames test and the in vitro HGPRT forward mutation assay in Chinese hamster lung cells; it did not produce significant increases in chromosomal aberrations in the in vitro Chinese hamster lung cell assay; it was negative in the in vivo chromosomal aberration assay and in the in vivo micronucleus test in Chinese hamster bone marrow; it was negative in the in vivo mouse micronucleus assay; and it did not induce unscheduled DNA synthesis in hepatocytes from rats given gabapentin.

No adverse effects on fertility or reproduction were observed in rats at doses up to 2000 mg/kg (approximately 5 times the maximum recommended human dose on a mg/m2 basis).

Pregnancy

Pregnancy Category C

Gabapentin has been shown to be fetotoxic in rodents, causing delayed ossification of several bones in the skull, vertebrae, forelimbs, and hindlimbs. These effects occurred when pregnant mice received oral doses of 1000 or 3000 mg/kg/day during the period of organogenesis, or approximately 1 to 4 times the maximum dose of 3600 mg/day given to epileptic patients on a mg/m2 basis. The no-effect level was 500 mg/kg/day or approximately ½ of the human dose on a mg/m2 basis.

When rats were dosed prior to and during mating, and throughout gestation, pups from all dose groups (500, 1000, and 2000 mg/kg/day) were affected. These doses are equivalent to less than approximately 1 to 5 times the maximum human dose on a mg/m2 basis. There was an increased incidence of hydroureter and/or hydronephrosis in rats in a study of fertility and general reproductive performance at 2000 mg/kg/day with no effect at 1000 mg/kg/day, in a teratology study at 1500 mg/kg/day with no effect at 300 mg/kg/day, and in a perinatal and postnatal study at all doses studied (500, 1000, and 2000 mg/kg/day). The doses at which the effects occurred are approximately 1 to 5 times the maximum human dose of 3600 mg/day on a mg/m2 basis; the no-effect doses were approximately 3 times (Fertility and General Reproductive Performance study) and approximately equal to (Teratogenicity study) the maximum human dose on a mg/m2 basis. Other than hydroureter and hydronephrosis, the etiologies of which are unclear, the incidence of malformations was not increased compared to controls in offspring of mice, rats, or rabbits given doses up to 50 times (mice), 30 times (rats), and 25 times (rabbits) the human daily dose on a mg/kg basis, or 4 times (mice), 5 times (rats), or 8 times (rabbits) the human daily dose on a mg/m2 basis.

In a teratology study in rabbits, an increased incidence of postimplantation fetal loss occurred in dams exposed to 60, 300, and 1500 mg/kg/day, or less than approximately ¼ to 8 times the maximum human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women. This drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

To provide information regarding the effects of in utero exposure to Neurontin, physicians are advised to recommend that pregnant patients taking Neurontin enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.

Use in Nursing Mothers

Gabapentin is secreted into human milk following oral administration. A nursed infant could be exposed to a maximum dose of approximately 1 mg/kg/day of gabapentin. Because the effect on the nursing infant is unknown, Neurontin should be used in women who are nursing only if the benefits clearly outweigh the risks.

Pediatric Use

Safety and effectiveness of Neurontin (gabapentin) in the management of postherpetic neuralgia in pediatric patients have not been established.

Effectiveness as adjunctive therapy in the treatment of partial seizures in pediatric patients below the age of 3 years has not been established (see CLINICAL PHARMACOLOGY, Clinical Studies).

Geriatric Use

The total number of patients treated with Neurontin in controlled clinical trials in patients with postherpetic neuralgia was 336, of which 102 (30%) were 65 to 74 years of age, and 168 (50%) were 75 years of age and older. There was a larger treatment effect in patients 75 years of age and older compared with younger patients who received the same dosage. Since gabapentin is almost exclusively eliminated by renal excretion, the larger treatment effect observed in patients ≥75 years may be a consequence of increased gabapentin exposure for a given dose that results from an age-related decrease in renal function. However, other factors cannot be excluded. The types and incidence of adverse events were similar across age groups except for peripheral edema and ataxia, which tended to increase in incidence with age.

Clinical studies of Neurontin in epilepsy did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly pat