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Ideally, patients will make their own decisions on the basis of a careful assessment of potential benefits and burdens, consistent with legal and ethical norms that permit patients to accept or forgo specific medical interventions. In , fluoride was documented as a neurotoxin that could be hazardous to child development, along with 10 other industrial chemicals, including lead, arsenic, toluene, and methylmercury. Food First is one of the primary think tanks working to build support for food sovereignty. If blood sugar can be measured immediately and quickly, perform a finger or heel stick. These data underscore the importance of lifestyle counseling and screening for hormonal deficits during long-term survivors' follow-up evaluations. Depending on the procedure, surgery can cause mechanical or physiologic barriers to adequate nutrition, such as a short gut that results in malabsorption after bowel resection. When synthesized by monocyte-macrophages, calcitriol acts locally as a cytokine , modulating body defenses against microbial invaders by stimulating the innate immune system.

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Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers.

Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs e. Monitor these patients for signs of hypotension after initiating or titrating the dosage of Duragesic.

In patients with circulatory shock, Duragesic may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Duragesic in patients with circulatory shock. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with Duragesic. Avoid the use of Duragesic in patients with impaired consciousness or coma.

Duragesic may produce bradycardia. Monitor patients with bradyarrhythmias closely for changes in heart rate, particularly when initiating therapy with Duragesic. A clinical pharmacology study with Duragesic in patients with cirrhosis has shown that systemic fentanyl exposure increased in these patients.

Because of the long half-life of fentanyl when administered as Duragesic and hepatic metabolism of fentanyl, avoid use of Duragesic in patients with severe hepatic impairment. Insufficient information exists to make precise dosing recommendations regarding the use of Duragesic in patients with impaired hepatic function. Therefore, to avoid starting patients with mild to moderate hepatic impairment on too high of a dose, start with one half of the usual dosage of Duragesic.

Closely monitor for signs of sedation and respiratory depression, including at each dosage increase. A clinical pharmacology study with intravenous fentanyl in patients undergoing kidney transplantation has shown that patients with high blood urea nitrogen level had low fentanyl clearance.

Because of the long half-life of fentanyl when administered as Duragesic, avoid the use of Duragesic in patients with severe renal impairment. Insufficient information exists to make precise dosing recommendations regarding the use of Duragesic in patients with impaired renal function.

Therefore, to avoid starting patients with mild to moderate renal impairment on too high of a dose, start with one half of the usual dosage of Duragesic. Closely monitor for signs of sedation and respiratory depression, including at each dosage increase [see Dosage and Administration 2. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis for worsening symptoms. Monitor patients with a history of seizure disorders for worsened seizure control during Duragesic therapy.

Duragesic may impair the mental or physical abilities required for the performance of potentially dangerous activities, such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of the Duragesic and know how they will react to the medication [see Patient Counseling Information 17 ].

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of Duragesic was evaluated in patients who took at least one dose of Duragesic in a multicenter, double-blind, randomized, placebo-controlled clinical trial of Duragesic. This trial examined patients over 40 years of age with severe pain induced by osteoarthritis of the hip or knee and who were in need of and waiting for joint replacement.

General disorders and administration site conditions: Reproductive system and breast disorders: Respiratory, thoracic and mediastinal disorders: Skin and subcutaneous tissue disorders: The safety of Duragesic was evaluated in three open-label trials in pediatric patients with chronic pain, 2 years of age through 18 years of age.

The following adverse reactions have been identified during post-approval use of Duragesic. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Respiratory, Thoracic, and Mediastinal Disorders: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Anaphylaxis, including anaphylactic shock, has been reported with ingredients contained in Duragesic. Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions 5.

Available data with Duragesic in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, fentanyl administration to pregnant rats during organogenesis was embryocidal at doses within the range of the human recommended dosing. When administered during gestation through lactation fentanyl administration to pregnant rats resulted in reduced pup survival and developmental delays at doses within the range of the human recommended dosing.

No evidence of malformations were noted in animal studies completed to date [ see Data ]. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight.

The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions 5.

Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate.

Duragesic is not recommended for use in pregnant women during or immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics, including Duragesic, can prolong labor through actions that temporarily reduce the strength, duration, and frequency of uterine contractions.

However, this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. There are no adequate and well-controlled studies in pregnant women.

Duragesic should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Chronic maternal treatment with fentanyl during pregnancy has been associated with transient respiratory depression, behavioral changes, or seizures characteristic of neonatal abstinence syndrome in newborn infants. Symptoms of neonatal respiratory or neurological depression were no more frequent than expected in most studies of infants born to women treated acutely during labor with intravenous or epidural fentanyl.

Transient neonatal muscular rigidity has been observed in infants whose mothers were treated with intravenous fentanyl. In contrast, the intravenous administration of fentanyl 0, 0. There was no clear evidence of teratogenicity noted. Pregnant female New Zealand White rabbits were treated with fentanyl 0, 0. Fentanyl produced a slight decrease in the body weight of the live fetuses at the high dose, which may be attributed to maternal toxicity.

Under the conditions of the assay, there was no evidence for fentanyl induced adverse effects on embryo-fetal development at doses up to 0. The potential effects of fentanyl on prenatal and postnatal development were examined in the rat model. Female Wistar rats were treated with 0, 0. Both the mid-dose and high-dose of fentanyl animals demonstrated alterations in some physical landmarks of development delayed incisor eruption and eye opening and transient behavioral development decreased locomotor activity at Day 28 which recovered by Day The mid-dose and the high-dose are 0.

Fentanyl is excreted in human milk; therefore, Duragesic is not recommended for use in nursing women because of the possibility of effects in their infants. Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with Duragesic.

Monitor infants exposed to Duragesic through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped.

Due to effects of androgen deficiency, chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions 6. The safety and effectiveness of Duragesic in children under 2 years of age have not been established.

To guard against excessive exposure to Duragesic by young children, advise caregivers to strictly adhere to recommended Duragesic application and disposal instructions [see Dosage and Administration 2. Clinical studies of Duragesic did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, use caution when selecting a dosage for an elderly patient, 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. Data from intravenous studies with fentanyl suggest that the elderly patients may have reduced clearance and a prolonged half-life.

Moreover, elderly patients may be more sensitive to the active substance than younger patients. A study conducted with the Duragesic patch in elderly patients demonstrated that fentanyl pharmacokinetics did not differ significantly from young adult subjects, although peak serum concentrations tended to be lower and mean half-life values were prolonged to approximately 34 hours [see Clinical Pharmacology Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration.

Titrate the dosage of Duragesic slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions 5. Fentanyl is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function.

Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. The effect of hepatic impairment on the pharmacokinetics of Duragesic has not been fully evaluated. Because there is in-vitro and in-vivo evidence of extensive hepatic contribution to the elimination of Duragesic, hepatic impairment would be expected to have significant effects on the pharmacokinetics of Duragesic.

Avoid use of Duragesic in patients with severe hepatic impairment [see Dosage and Administration 2. The effect of renal impairment on the pharmacokinetics of Duragesic has not been fully evaluated.

Because there is in-vivo evidence of renal contribution to the elimination of Duragesic, renal impairment would be expected to have significant effects on the pharmacokinetics of Duragesic.

Avoid the use of Duragesic in patients with severe renal impairment [see Dosage and Administration 2. Duragesic contains fentanyl, a substance with a high potential for abuse similar to other opioids including hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, and tapentadol.

Duragesic can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions 5. The high drug content in long-acting formulations adds to the risk of adverse outcomes from abuse and misuse.

All patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated "loss" of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare providers.

Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control. Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare providers should be aware that addiction may be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction.

Duragesic, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

Duragesic is intended for transdermal use only. Abuse of Duragesic poses a risk of overdose and death. This risk is increased with concurrent abuse of Duragesic with alcohol and other central nervous system depressants [see Warnings and Precautions 5.

Intentional compromise of the transdermal delivery system may result in the uncontrolled delivery of fentanyl and pose a significant risk to the abuser that could result in overdose and death [see Warnings and Precautions 5.

Abuse may occur by applying the transdermal system in the absence of legitimate purpose, or by swallowing, snorting or injecting fentanyl extracted from the transdermal system. Both tolerance and physical dependence can develop during chronic opioid therapy.

Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia in the absence of disease progression or other external factors. Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects. Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity e.

Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage. Duragesic should not be abruptly discontinued [see Dosage and Administration 2. If Duragesic is abruptly discontinued in a physically-dependent patient, a withdrawal syndrome may occur.

Some or all of the following can characterize this syndrome: Other signs and symptoms also may develop, including: Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms [see Use in Specific Populations 8. Acute overdose with Duragesic can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death.

Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Clinical Pharmacology Give primary attention to the reestablishment of a patent airway and institution of assisted or controlled ventilation, if needed.

Employ other supportive measures including oxygen and vasopressors in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques. Once stable, ensure examine the patient and ensure that all Duragesic Transdermal Systems have been removed.

The opioid antagonists, such as naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to fentanyl overdose, administer an opioid antagonist. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to fentanyl overdose.

Because the duration of opioid reversal is expected to be less than the duration of action of fentanyl in Duragesic, carefully monitor the patient until spontaneous respiration is reliably reestablished. Therefore, management of an overdose must be monitored accordingly, at least 72 to 96 hours beyond the overdose. In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome.

The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be initiated with care and by titration with smaller than usual doses of the antagonist. Duragesic fentanyl transdermal system contains fentanyl, an opioid agonist, available as a patch for transdermal administration.

The composition per unit area of all system sizes is identical. The molecular weight of fentanyl base is The pKa is 8. The chemical name is N-Phenyl-N- 1- 2-phenylethyl piperidinyl propanamide. The structural formula is:. Duragesic is a rectangular transparent unit comprised of a clear siliconized polyethylene terephthalate protective liner and two functional layers. Proceeding from the outer surface toward the surface adhering to skin, these functional layers are:.

Before use, a protective liner covering the adhesive layer is removed and discarded. Fentanyl is an opioid agonist. Fentanyl interacts predominately with the opioid mu-receptor.

These mu-binding sites are distributed in the human brain, spinal cord, and other tissues. Fentanyl produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation.

Fentanyl causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic e. Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations. In clinical trials of non-opioid tolerant subjects treated with Duragesic, 13 subjects experienced hypoventilation. In these studies, the incidence of hypoventilation was higher in nontolerant women 10 than in men 3 and in subjects weighing less than 63 kg 9 of Although subjects with prior impaired respiration were not common in the trials, they had higher rates of hypoventilation.

In addition, post-marketing reports have been received that describe opioid-naive post-operative patients who have experienced clinically significant hypoventilation and death with Duragesic. Hypoventilation can occur throughout the therapeutic range of fentanyl serum concentrations, especially for patients who have an underlying pulmonary condition or who receive concomitant opioids or other CNS drugs associated with hypoventilation.

The use of Duragesic is contraindicated in patients who are not tolerant to opioid therapy. Fentanyl causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone is increased to the point of spasm, resulting in constipation.

Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase. Fentanyl produces peripheral vasodilation, which may result in orthostatic hypotension or syncope. Histamine assays and skin wheal testing in clinical studies indicate that clinically significant histamine release rarely occurs with fentanyl administration.

They also stimulate prolactin, growth hormone GH secretion, and pancreatic secretion of insulin and glucagon. Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility.

The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions 6.

Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive. The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with potent agonist opioids.

There is a relationship between increasing fentanyl plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration 2. Duragesic is a drug-in-adhesive matrix designed formulation.

Fentanyl is released from the matrix at a nearly constant amount per unit time. The concentration gradient existing between the matrix and the lower concentration in the skin drives drug release. Fentanyl moves in the direction of the lower concentration at a rate determined by the matrix and the diffusion of fentanyl through the skin layers.

While the actual rate of fentanyl delivery to the skin varies over the hour application period, each system is labeled with a nominal flux which represents the average amount of drug delivered to the systemic circulation per hour across average skin. While there is variation in dose delivered among patients, the nominal flux of the systems Following Duragesic application, the skin under the system absorbs fentanyl, and a depot of fentanyl concentrates in the upper skin layers.

Fentanyl then becomes available to the systemic circulation. Serum fentanyl concentrations increase gradually following initial Duragesic application, generally leveling off between 12 and 24 hours and remaining relatively constant, with some fluctuation, for the remainder of the hour application period.

Peak serum concentrations of fentanyl generally occurred between 20 and 72 hours after initial application see Table 7. Serum fentanyl concentrations achieved are proportional to the Duragesic delivery rate. With continuous use, serum fentanyl concentrations continue to rise for the first two system applications.

By the end of the second hour application, a steady-state serum concentration is reached and is maintained during subsequent applications of a patch of the same size see Figure 1. Patients reach and maintain a steady-state serum concentration that is determined by individual variation in skin permeability and body clearance of fentanyl.

Continued absorption of fentanyl from the skin accounts for a slower disappearance of the drug from the serum than is seen after an IV infusion, where the apparent half-life is approximately 7 range 3—12 hours. Fentanyl plasma protein binding capacity decreases with increasing ionization of the drug. Alterations in pH may affect its distribution between plasma and the central nervous system.

Fentanyl accumulates in the skeletal muscle and fat and is released slowly into the blood. Fentanyl is metabolized primarily via human cytochrome P 3A4 isoenzyme system. In humans, the drug appears to be metabolized primarily by oxidative N-dealkylation to norfentanyl and other inactive metabolites that do not contribute materially to the observed activity of the drug.

Skin does not appear to metabolize fentanyl delivered transdermally. Moreover elderly patients may be more sensitive to the active substance than younger patients. A study conducted with the Duragesic fentanyl transdermal patch in elderly patients demonstrated that fentanyl pharmacokinetics did not differ significantly from young adult subjects, although peak serum concentrations tended to be lower and mean half-life values were prolonged to approximately 34 hours.

In older pediatric patients, the pharmacokinetic parameters were similar to that of adults. However, these findings have been taken into consideration in determining the dosing recommendations for opioid-tolerant pediatric patients 2 years of age and older. For pediatric dosing information, refer to [see Dosage and Administration 2.

Information on the effect of hepatic impairment on the pharmacokinetics of Duragesic is limited. Avoid use of Duragesic in patients with severe hepatic impairment [see Dosing and Administration 2.

Information on the effect of renal impairment on the pharmacokinetics of Duragesic is limited. An inverse relationship between blood urea nitrogen level and fentanyl clearance was found. Avoid the use of Duragesic in patients with severe renal impairment [see Dosing and Administration 2. The interaction between ritonavir, a CPY3A4 inhibitor, and fentanyl was investigated in eleven healthy volunteers in a randomized crossover study.

Subjects received oral ritonavir or placebo for 3 days. The ritonavir dose was mg three times a day on Day 1 and mg three times a day on Day 2 followed by one morning dose of mg on Day 3. Naloxone was administered to counteract the side effects of fentanyl.

The concomitant use of transdermal fentanyl with all CYP3A4 inhibitors such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazadone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, verapamil, or grapefruit juice may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. Carefully monitor patients receiving Duragesic and any CYP3A4 inhibitor for signs of respiratory depression for an extended period of time and adjust the dosage if warranted [see Boxed Warning and Warnings and Precautions 5.

The potential effects of fentanyl on male and female fertility were examined in the rat model via two separate experiments. In the male fertility study, male rats were treated with fentanyl 0, 0. In the female fertility study, female rats were treated with fentanyl 0, 0.

Analysis of fertility parameters in both studies indicated that an intravenous dose of fentanyl up to 0. In a separate study, a single daily bolus dose of fentanyl was shown to impair fertility in rats when given in intravenous doses of 0. Duragesic as therapy for pain due to cancer has been studied in patients. Individual patients have used Duragesic continuously for up to days.

At one month after initiation of Duragesic therapy, patients generally reported lower pain intensity scores as compared to a pre-study analgesic regimen of oral morphine. In the pediatric population, the safety of Duragesic has been evaluated in patients with chronic pain 2—18 years of age. Twenty-five patients were treated with Duragesic for at least 4 months and 9 patients for more than 9 months. Duragesic fentanyl transdermal system is supplied in cartons containing 5 individually packaged systems.

See chart for information regarding individual systems. Store in original unopened pouch. Inform patients that the use of Duragesic, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions 5. Instruct patients not to share Duragesic with others and to take steps to protect Duragesic from theft or misuse.

Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting Duragesic or when the dosage is increased, and that it can occur even at recommended dosages [see Warnings and Precautions 5. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.

Inform patients that accidental exposure, especially in children, may result in respiratory depression or death [see Warnings and Precautions 5. Instruct patients to take steps store Duragesic securely and to dispose of unused Duragesic by flushing down the toilet [see Dosage and Administration 2.

Duragesic can be accidentally transferred to children. Instruct patients to take special precautions to avoid accidental contact when holding or caring for children.

Instruct patients that, if the patch dislodges and accidentally sticks to the skin of another person, to immediately take the patch off, wash the exposed area with water and seek medical attention for the accidentally exposed individual as accidental exposure may lead to death or other serious medical problems. Instruct patients to refer to the Instructions for Use for proper disposal of Duragesic. To properly dispose of a used patch, instruct patients to remove it, fold so that the adhesive side of the patch adheres to itself, and immediately flush down the toilet.

Unused patches should be removed from their pouches, the release liners removed, the patches folded so that the adhesive side of the patch adheres to itself, and immediately flushed down the toilet.

Inform patients that deaths have occurred from accidental exposure to Duragesic Transdermal Systems discarded in the trash. Instruct patients to dispose of any patches remaining from a prescription as soon as they are no longer needed. Inform patients and caregivers that potentially fatal additive effects may occur if Duragesic is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider [see Warnings and Precautions 5.

Inform patients that opioids could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms and signs of serotonin syndrome, and to seek medical attention right away if symptoms develop. Instruct patients to inform their healthcare providers if they are taking, or plan to take serotonergic medications [see Warnings and Precautions 5.

Inform patients to avoid taking Duragesic while using any drugs that inhibit monoamine oxidase. Fluoride-induced chronic renal failure. American Journal of Kidney Disorders Latham MC, Grech P. The effects of excessive fluoride intake. American Journal of Public Health A roentgenologic study of a human population exposed to high-fluoride domestic water: Osteoporosis--an early radiographic sign of endemic fluorosis.

Skeletal Radiology 15 5: Fluoride osteosclerosis from drinking water. Paleopathology of skeletal fluorosis. American Journal of Physical Anthropology 4: Endemic fluorosis in Kweichow, China. Misra UK, et al. Endemic fluorosis presenting as cervical cord compression. Archives of Environmental Health Mithal A, et al. Radiological spectrum of endemic fluorosis: Skeletal Radiology 22 4: Skeletal fluorosis among indians of the American Southwest.

Ossification of the ligamentum flavum as a result of fluorosis causing myelopathy: Pandit CG, et al. Endemic fluorosis in South India. Indian Journal of Medical Research Pinet A, Pinet F. Endemic fluorosis in the Sahara. Sauerbrunn BJ, et al.

Chronic fluoride intoxication with fluorotic radiculomyelopathy. Savas S, et al. Endemic fluorosis in Turkish patients: Rheumatology International 21 1: Shortt HE, et al. Endemic fluorosis in the Madras presidency.

Neurological complications of skeletal fluorosis with special reference to lesions in the cervical region. Fluorosis in Nalgonda district, Hyderabad-Deccan. British Medical Journal ii Dec Singh A, Jolly SS. Chronic toxic effects on the skeletal system. Fluorides and Human Health. Singh A, et al. Epidemiological, clinical and biochemical study of chronic fluoride intoxication in Punjab.

Skeletal fluorosis and its neurological complications. Periostitis deformans due to wine fluorosis. Stevenson CA, Watson R. Susheela AK, et al. Prevalence of endemic fluorosis with gastro-intestinal manifestations in people living in some North-Indian villages. Endemic chronic fluoride toxicity and dietary calcium deficiency interaction syndromes of metabolic bone disease and deformities in India: Indian Journal of Pediatrics Teotia SPS, et al.

Symposium on the non-skeletal phase of chronic fluorosis: Further observations on endemic fluoride-induced osteopathies in children. Xu RQ, et al. Relations between environment and endemic fluorosis in Hohot region, Inner Mongolia. Incipient fluorine intoxication from drinking water. Acta Medica Scandinavica Wang W, et al. Ossification of the transverse atlantal ligament associated with fluorosis: Endemic fluorosis of the skeleton: American Journal of Roentgenology 1: Endemic fluorosis with neurological complications in a Hampshire man.

Journal of Neurology, Neurosurgery and Psychiatry Whyte MP, et al. Skeletal fluorosis and instant tea. American Journal of Medicine Yang L, et al. Developing environmental health indicators as policy tools for endemic fluorosis management in the People's Republic of China.

Environmental Geochemistry and Health 25 3: Occupational Fluorosis back to top. Boillat MA, et al. Radiological criteria of industrial fluorosis. Czerwinski E, et al. Bone and joint pathology in fluoride-exposed workers.

Archives of Environmental Health 43 5: Czerwinski E, Lankosz W. Skeletal changes in industrial and endemic fluorosis. Fluoride-induced changes in 60 retired aluminum workers. Derryberry OM, et al. Fluoride exposure and worker health. Archives of Environmental Health 6: Franke J, et al. Occupational fluorosis through 50 years: American Journal of Industrial Medicine 3 2: Journal of Occupational Medicine Kaltreider NL, et al.

Health survey of aluminum workers with special reference to fluoride exposure. Journal of Occupational Medicine 14 7: Massive fluorosis of bones and ligaments. Runge H, Franke J. Radiological modifications of the skeletal system among aluminum smelter workers: A 15 year retrospective study. Tartatovskaya LY, et al. Clinico-hygiene assessment of the combined effect on the body of vibration and fluorine. Noise and Vibration Bulletin Zhiliang Y, et al.

Industrial fluoride pollution in the metallurgical industry in China. Livestock Fluorosis back to top. Fluorosis in dairy cattle. The Veterinary Record Effects on livestock of air contamination caused by fluoride fumes. Krook L, Maylin GA. Chronic fluoride poisoning in Cornwall Island cattle. Cornell Veterinarian 69 Suppl 8: The fluorosis problem in livestock production. Committee on Animal Nutrition, Agricultural Board.

A critical study of the literature on fluoride toxicology with respect to cattle damage. American Journal of Veterinary Research Clinical aspects of fluorosis in horses. Journal of the American Veterinary Association Shupe JL, et al. The effect of fluorine on dairy cattle II. Clinical and pathologic effects. Effects of fluoride on livestock. Animal Studies back to top.

Effects of fluoride on mechanical properties of femoral bone in growing rats. Burnell TW, et al. Effect of dietary fluorine on growth, blood and bone characteristics of growing-finishing pigs. Journal of Animal Science Effects of fluoride treatment on bone strength. Journal of Bone and Mineral Research 5 Suppl 1: Gedalia I, et al. Effects of estrogen on bone composition in rats at low and high fluoride intake. Giavaresi G, et al. The mechanical properties of fluoride-treated bone in the ovariectomized rat.

Calcified Tissue International Lafage MH, et al. Comparison of alendronate and sodium fluoride effects on cancellous and cortical bone in minipigs. Journal of Clinical Investigation Mosekilde L, et al. Compressive strength, ash weight, and volume of vertebral trabecular bone in experimental fluorosis in pigs. Riggins RS, et al. The effect of fluoride supplementation on the strength of osteopenic bone.

In vitro sodium fluoride exposure decreases torsional and bending strength and increases ductility of mouse femora. Journal of Biomechanics 33 2: Sogaard CH, et al. Effects of fluoride on rat vertebral body biomechanical competence and bone mass. Turner CH, et al.

Combined effects of diets with reduced calcium and phosphate and increased fluoride intake on vertebral bone strength and histology in rats. Calcified Tissue International 69 1: Fluoride treatment increased serum IGF-1, bone turnover, and bone mass, but not bone strength, in rabbits. Calcified Tissue International 61 1: High fluoride intakes cause osteomalacia and diminished bone strength in rats with renal deficiency. Reductions in bone strength after fluoride treatment are not reflected in tissue-level acoustic measurements.

Fluoride reduces bone strength in older rats. Journal of Dental Research 74 8: On fluoride and bone strength letter. The effects of fluoridated water on bone strength. Journal of Orthopaedic Research 10 4: Walsh WR, Guzelsu N.

The role of ions and mineral-organic interfacial bonding on the compressive properties of cortical bone. Bio-Medical Materials and Engineering 3: Wolinsky I, et al.

Effects of fluoride on metabolism and mechanical properties of rat bone. American Journal of Physiology 1: Human Clinical Trials back to top. Bayley TA, et al. Dambacher MA, et al. Long-term fluoride therapy of postmenopausal osteoporosis. Gerster JC, et al. Bilateral fractures of femoral neck in patients with moderate renal failure receiving fluoride for spinal osteoporosis.

Gutteridge DH, et al. Osteoporosis International 13 2: Spontaneous hip fractures in fluoride-treated patients: Haguenauer D, et al. Fluoride for the treatment of postmenopausal osteoporotic fractures: Osteoporosis International 11 9: Increased incidence of hip fracture in osteoporotic women treated with sodium fluoride. Journal of Bone and Mineral Research 4: Inkovaara J, et al. Prophylactic fluoride treatment and aged bones. British Medical Journal 3 Kleerekoper M, et al.

A randomized trial of sodium fluoride as a treatment for postmenopausal osteoporosis. Osteoporosis International 1 3: Meunier PJ, et al. Fluoride salts are no better at preventing new vertebral fractures than calcium-vitamin D in postmenopausal osteoporosis: O'Duffy JD, et al. Mechanism of acute lower extremity pain syndrome in fluoride-treated osteoporotic patients. Orcel P, et al. Stress fractures of the lower limbs in osteoporotic patients treated with fluoride.

Pak CY, et al. Comparison of nonrandomized trials with slow-release sodium fluoride with a randomized placebo-controlled trial in postmenopausal osteoporosis. Journal of Bone and Mineral Research 11 2: Treatment of postmenopausal osteoporosis with slow-release sodium fluoride. Final report of a randomized controlle d trial. Riggs BL, et al.

New England Journal of Medicine Rubin CD, et al. Sustained-release sodium fluoride in the treatment of the elderly with established osteoporosis. Schnitzler CM, et al. Bone fragility of the peripheral skeleton during fluoride therapy for osteoporosis.

Schnitzler CM, Solomon L. Trabecular stress fractures during fluoride therapy for osteoporosis. Skeletal Radioliology 14 4: Epidemiological Studies back to top. Water fluoride concentration and fracture of the proximal femur.

Journal of Epidemiology and Community Health Water fluoridation and hip fracture. A reanalysis of data presented in paper. Danielson C, et al. Hip fractures and fluoridation in Utah's elderly population. Journal of the American Medical Association 6: Hegmann KT, et al. The effects of fluoridation on degenerative joint disease DJD and hip Fractures. Abstract 71 of the 33rd annual meeting of the Society for Epidemiological Research.

American Journal of Epidemiology S Jacobsen SJ, et al. The association between water fluoridation and hip fracture among white women and men aged 65 years and older; a national ecologic study. Annals of Epidemiology 2: Regional variation in the incidence of hip fracture: US white women aged 65 years and olders. Journal of the American Medical Association 4: Fluorine concentration in drinking water and fractures in the elderly. Risk factors for fractures in the elderly. An elaboration of the study referred to in the JAMA letter.

Kurttio PN, et al. Exposure to natural fluoride in well water and hip fracture: A cohort analysis in Finland. American Journal of Epidemiology 8: Hip fractures in relation to water fluoridation: Suarez-Almazor M, et al. The fluoridation of drinking water and hip fracture hospitalization rates in two Canadian communities. The authors of this study conclude there is no association between fluoridation and hip fracture.

However, their own data reveals a significant increase in hip fracture for men living in the fluoridated area. Effect of long-term exposure to fluoride in drinking water on risks of bone fractures.

Journal of Bone and Mineral Research 16 5: Sowers MR, et al. The relationship of bone mass and fracture history to fluoride and calcium intake: American Journal of Clinical Nutrition Sowers M, et al. A prospective study of bone mineral content and fracture in communities with differential fluoride exposure.

American Journal of Epidemiology Journal of Nutrition See notes and quotes below. Arnala I, et al. Hip fracture incidence not affected by fluoridation. Osteofluorosis studied in Finland. Acta Orthopaedica Scandinavica Effects of fluoridated drinking water on bone mass and fractures: Journal of Bone and Mineral Research 10 7: Feskanich D, et al. Use of toenail fluoride levels as an indicator for the risk of hip and forearm fractures in women. While this study didn't find an association between water fluoride and hip fracture, it did find an association - albeit non-significant 1.

Hillier S, et al. Fluoride in drinking water and risk of hip fracture in the UK: Hip fracture incidence before and after the fluoridation of the public water supply, Rochester, Minnesota.

Karagas MR, et al. Patterns of fracture among the United States elderly: Geographic and fluoride effects. Annals of Epidemiology 6 3: See abstract See critique of study. Lehmann R, et al.

Bone mineral density and hip fracture incidence. Madans J, et al. The relationship between hip fracture and water fluoridation: Phipps KR, et al. Community water fluoridation, bone mineral density and fractures: British Medical Journal This study reported a decreased incidence of hip fracture in fluoridated areas.

However, as with Feskanich and Karagas , the study also found an association between fluoridation and other types of fracture - in this case, wrist fracture. Bernstein DS, et al. Prevalence of osteoporosis in high- and low-fluoride areas in North Dakota. Belanger LF, et al. Rachitomimetic effects of fluoride feeding on the skeletal tissues of growing pigs. American Journal of Pathology Burkhart JM, Jowsey J. Effect of variations in calcium intake on the skeleton of fluoride-fed kittens.

Journal of Laboratory and Clinical Medicine Chachra D, et al. The effect of fluoride treatment on bone mineral in rabbits. Comar CL, et al. Effects of fluorine on calcium metabolism and bone growth in pigs. American Journal of Anatomy Kragstrup J, et al. Experimental osteo-fluorosis in the domestic pig: Journal of Dental Research Fratzl P, et al. Effects of sodium fluoride and alendronate on the bone mineral in minipigs: Golub L, et al.

The effect of sodium fluoride on the rates of synthesis and degradation of bone collagen in tissue culture. Proceedings of the Society for Experimental Biology and Medicine Guggenheim K, et al. The effect of fluoride on bone of rats fed diets deficient in calcium or phosphorus.

Henrikson PA, et al. Fluoride and nutritional osteoporosis. Ittel TH, et al. Effect of fluoride on aluminum-induced bone disease in rats with renal failure. Jiang Y, et al. Effects of low-dose long-term sodium fluoride preventive treatment on rat bone mass and biomechanical properties.

Kierdorf U, et al. Fluoride content and mineralization of red deer Cervus elaphus antlers and pedicles from fluoride polluted and uncontaminated regions. Archives of Environmental Contamination and Toxicology Ream JL, et al. Fluoride ingestion during multiple pregnancies and lactations: Virchows Archiv B The effects of short-term fluoride ingestion on bone formation and resorption in the rat femur. Cell and Tissue Research Robin JC, et al.

Studies on osteoporosis III. Effect of estrogens and fluoride. Journal of Medicine X-ray absorption and x-ray fluorescence micro-analysis of mineralized tissue of rats which have ingested fluoridated water. Acta Pathologica et Microbiologica Scandinavica Effect on sodium fluoride on collagen cross-link precursors. Snow GR, Anderson C. Short-term chronic fluoride administration and trabecular bone remodeling in beagles: Calcified Tissue International 38 4: Susheela AK, Jha M.

Cellular and histological characteristics of osteoid formed in experimental fluoride poisoning. Turner RT, et al. The effects of fluoride on bone and implant histomorphometry in growing rats. Journal of Bone and Mineral Research 4 4: Effect of fluoride on collagen synthesis in the rat.

Research and Experimental Medicine 1: Fluoride ion effect on interfacial bonding and mechanical properties of bone. Journal of Biomechanics Krook L, Minor RR. Fluoride and alkaline phosphatase. Balena R, et al. Effects of different regimens of sodium fluoride treatment for osteoporosis on the structure, remodeling and mineralization of bone.

Osteoporosis International 8 5: The effects of fluoride therapy on metabolic bone disease. Clinical Orthopaedics and Related Research Boivin G, et al.

Relationship between bone fluoride content and histological evidence of calcification defects in osteoporotic women treated long term with sodium fluoride. Osteoporosis International 3 4: Cass RM, et al. New bone formation in osteoporosis following treatment with sodium fluoride.

Compston JE, et al. Osteomalacia developing during treatment of osteoporosis with sodium fluoride and vitamin D. Abnormal bone mineralization after fluoride treatment in osteoporosis: Journal of Bone and Mineral Research 9 Is fluoride treatment justified today? Calcified Tissue International 49 Suppl: Jowsey J, et al. Effect of combined therapy with sodium fluoride, vitamin D and calcium in osteoporosis.

American Journal of Medicine 53 1: Some results of the effect of fluoride on bone tissue in osteoporosis. Journal of Clinical Endocrinology Effects of sodium fluoride, vitamin D, and calcium on cortical bone remodeling in osteoporotic patients. Fluoride and Bone - Quantity Versus Quality. Lundy MW, et al. Histomorphometric analysis of iliac crest bone biopsies in placebo-treated versus fluoride-treated subjects. Patel S, et al. Fluoride pharmacokinetics and changes in lumbar spine and hip bone mineral density.

Treatment of osteoporosis with sodium fluoride: Bone and Mineral Research 2: Iliac bone biopsies at the time of periarticular stress fractures during fluoride therapy: Journal of Bone and Mineral Research 5 2: Marked decrease in trabecular bone quality after five years of sodium fluoride therapy--assessed by biomechanical testing of iliac crest bone biopsies in osteoporotic patients.

The microscopic morphology of fluoride-induced bone. Zerwekh JE, et al. Effect of slow-release sodium fluoride on cancellous bone histology and connectivity in osteoporosis. Fluoride Concentrations in Human Bone back to top. Alhava EM, et al. Bone fluoride in proximal femur fractures. Effects of fluoride on bone in Finland.

Histomorphometry of cadaver bone from low and high fluoride areas. Acta Orthopaedica Scandinavica 56 2: Fluoride content in human iliac bone: Journal of Bone and Mineral Research 3 5: Call RA, et al. Histological and chemical studies in man on effects of fluoride. Public Health Reports Charen J, et al. Bone fluoride concentrations associated with fluoridated drinking water. Calcified Tissue International 27 2: Cohen-Solal ME, et al. Fluoride and strontium accumulation in bone does not correlate with osteoid tissue in dialysis patients.

Nephrology Dialysis Transplantation Eble DM, et al. Fluoride concentrations in human and rat bone. Journal of Public Health Dentistry Glock GE, et al. The retention and elimination of fluoride in bones. Hefti A, Marthaler TM. Bone fluoride concentrations after 16 years of drinking water fluoridation. Caries Research 15 1: Jackson D, Weidman SM. Fluorine in human bone related to age and the water supply of different regions.

Journal of Pathological Bacteriology Fluoride levels in human rib bone: Canadian Journal of Public Health 65 5: Ng AHM, et al. Association between fluoride, magnesium, aluminum and bone quality in renal osteodystrophy.

Parkins FM, et al. Relationships of human plasma fluoride and bone fluoride to age. Richards A, et al. Normal age-related changes in fluoride content of vertebral trabecular bone - Relation to bone quality. Smith FA, et al. Age increase and fluoride content in human bone. Stein ID, Granik G. Relation of strength, porosity, and mineralization to fluoride content.

Wix P, Mohamedally SM. The significance of age-dependent fluoride accumulation in bone in relation to daily intake of fluoride. Zipkin L, et al.

Fluoride deposition in human bones after prolonged ingestion of fluoride in drinking water. US Public Health Reports F actors which Increase Accumulation of Fluoride in Bone: Annals of Internal Medicine 63 6: Kono K, et al. Urinary fluoride excretion in fluoride exposed workers with diminished renal function. Industrial Health 22 1: Noel C, et al. Spak CJ, et al. Renal clearance of fluoride in children and adolescents.

Welsch M, et al. Factors which Increase Accumulation of Fluoride in Bone: Nutritional Deficiencies back to top. The effects of fluoride and low calcium on the physical properties of the rat femur. The Anatomical Record Li G, Ren L. Likimani S, et al. The effects of protein deficiency and fluoride on bone mineral content of rat tibia. Calcified Tissue International 50 2: Marier JR, et al. Accumulation of skeletal fluoride and its implications.

The effects of sodium fluoride on bone breaking strength. Indian Journal of Pediatrics 65 3: Bucher JR, et al. Results and conclusions of the National Toxicology Program's rodent carcinogenicity studies with sodium fluoride. International Journal of Cancer 48 5: Technical report Series No. See executive summary See study See news articles. For commentary on NTP Study, see: A Statement of Concern.

Video-taped interview with Dr. Fluoridation and Bone Cancer. Liteplo RG, et al. Evaluation of risks to health from environmental exposure in Canada.

Journal of Environmental Science and Health. William Marcus,to Alan B. World Health Organ ization. Environmental Health Criteria World Health Organization, Geneva. Dose determination and carcinogenicity studies of sodium fluoride in Crl: CD-1 Mice and Crl: US Public Health Service. Maurer JK, et al. Confounded carcinogenicity study of sodium fluoride in CD-1 mice. Regulatory Toxicology and Pharmacology Two-year carcinogenicity study of sodium fluoride in rats. Journal of the National Cancer Institute Cancer Causes and Control See excerpt of study.

New Jersey Department of Health Environ. See Executive Summary See Study. Douglass CW, Joshipura K. Caution needed in fluoride and osteosarcoma study.

International trends in the incidence of bone cancer are not related to drinking water fluoridation. Fluoride exposure and childhood osteosarcoma: Hoover RN, et al. Bone cancer incidence rates in New York State: Osteosarcoma, seasonality, and environmental factors in Wisconsin, Regression analysis of cancer incidence rates and water fluoride in the U. International Agency for Research on Cancer. Journal of Epidemiology Relationship between fluoride concentration in drinking water and mortality rate from uterine cancer in Okinawa prefecture, Japan.

Journal of Epidemiology 6 4: Yang CY, et al. Fluoride in drinking water and cancer mortality in Taiwan. The biology and epidemiology of bone and oral cancer related to fluoridation. Grandjean P, Olsen J. Extended follow-up of cancer incidence in fluoride-exposed workers. See commentary on study. Grandjean P, et al. Cancer incidence and mortality in workers exposed to fluoride. Journal of the National Cancer Institute 84 Mortality and cancer morbidity after occupational fluoride exposure.

Studies where fluoride is accompanied with other contaminants, particularly PAH - the presumed causative agent. Risk of cancer in the Norwegian aluminum industry. International Journal of Cancer Armstrong B, et al. Lung cancer mortality and polynuclear aromatic hydrocarbons: A case-cohort study of aluminum production workers in Arvida, Quebec, Canada. Gibbs GW, Horowitz I. Lung cancer mortality in aluminum reduction plant workers. Mortality in aluminum reduction plant workers. Moulin JJ, et al.

A mortality study among potroom workers in a French aluminum reduction plant. International Archives of Occupational and Environmental Health Romundstad P, et al.

Cancer incidence among workers in six Norwegian aluminum plants. Scandinavian Jour nal of Worker and Environmental Health Ronneberg A, Andersen A. Mortality and cancer morbidity in workers from an aluminum smelter with prebaked carbon anodes - part II: Occupational and Environmental Medicine Spinelli JJ, et al. Mortality and cancer incidence in aluminum reduction plant workers. Sodium fluoride-induced chromosome aberrations in different stages of the cell cycle: Sodium fluoride and chromosome damage in vitro human lymphocyte and in vivo micronucleus assays.

Analysis of chromosomal abnormalities at anaphase-telophase induced by sodium fluoride in vitro. Caspary WJ, et al Mutagenic activity of fluorides in mouse lymphoma cells. Mutation Research 3: Cole J, et al. Crespi CL, et al. Sodium fluoride is a less efficient human cell mutagen at low concentrations. Environmental Molecular Mutagenesis 15 2: Department of Health and Human Services Review of fluoride benefits and risks.

Edwards SL, et al.

Subsequent Neoplasms