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hikma pharmaceuticals usa inc. - testosterone cypionate (unii: m0xw1ubi14) (testosterone - unii:3xmk78s47o) - testosterone cypionate 200 mg in 1 ml - testosterone cypionate injection, usp is indicated for replacement therapy in the male in conditions associated with symptoms of deficiency or absence of endogenous testosterone. - primary hypogonadism (congenital or acquired): testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome; or orchidectomy. - hypogonadotropic hypogonadism (congenital or acquired): gonadotropin or luteinizing hormone-releasing hormone (lhrh) deficiency, or pituitary-hypothalamic injury from tumors, trauma, or radiation. safety and efficacy of testosterone cypionate in men with “age-related hypogonadism” (also referred to as “late-onset hypogonadism”) have not been established. - known hypersensitivity to the drug - males with carcinoma of the breast - males with known or suspected carcinoma of the prostate gland - women who are pregnant (see precautions, pregnancy ) - patients with serious cardiac, hepatic or renal disease (see warnings ) testosterone cypionate injection contains testoster

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hikma pharmaceuticals usa inc. - acetazolamide sodium (unii: 429zt169uh) (acetazolamide - unii:o3fx965v0i) - acetazolamide 500 mg - for adjunctive treatment of: edema due to congestive heart failure; drug-induced edema; centrencephalic epilepsies (petit mal, unlocalized seizures); chronic simple (open-angle) glaucoma, secondary glaucoma, and preoperatively in acute angle-closure glaucoma where delay of surgery is desired in order to lower intraocular pressure. hypersensitivity to acetazolamide or any excipients in the formulation. since acetazolamide is a sulfonamide derivative, cross sensitivity between acetazolamide, sulfonamides and other sulfonamide derivatives is possible. acetazolamide for injection therapy is contraindicated in situations in which sodium and/or potassium blood serum levels are depressed, in cases of marked kidney and liver disease or dysfunction, in suprarenal gland failure, and in hyperchloremic acidosis. it is contraindicated in patients with cirrhosis because of the risk of development of hepatic encephalopathy. long-term administration of acetazolamide for injection is contraindicated in patients with chronic noncongestive angle-closure glaucoma since it may permit organic closure of the angle to occur while the worsening glaucoma is masked by lowered intraocular pressure.

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teva pharmaceuticals usa, inc. - amlodipine besylate (unii: 864v2q084h) (amlodipine - unii:1j444qc288) - amlodipine 2.5 mg - amlodipine besylate tablets are indicated for the treatment of hypertension, to lower blood pressure. lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. these benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including amlodipine besylate tablets. control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. many patients will require more than one drug to achieve blood pressure goals. for specific advice on goals and management, see published guidelines, such as those of the national high blood pressure education program’s joint national committee on prevention, detection, evaluation, and treatment of high blood pressure (jnc). numerous antihypertensive drugs, from a variety of pharmacologic

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teva pharmaceuticals usa, inc. - abacavir sulfate (unii: j220t4j9q2) (abacavir - unii:wr2tip26vs), lamivudine (unii: 2t8q726o95) (lamivudine - unii:2t8q726o95) - abacavir 600 mg - abacavir and lamivudine tablets, in combination with other antiretroviral agents, are indicated for the treatment of human immunodeficiency virus type 1 (hiv-1) infection. abacavir and lamivudine tablets are contraindicated in patients: - who have the hla-b*5701 allele [see warnings and precautions (5.1)]. - with prior hypersensitivity reaction to abacavir [see warnings and precautions (5.1)] or lamivudine. - with moderate or severe hepatic impairment [see use in specific populations (8.7)]. pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to abacavir and lamivudine tablets during pregnancy. healthcare providers are encouraged to register patients by calling the antiretroviral pregnancy registry (apr) at 1-800-258-4263. risk summary available data from the apr show no difference in the overall risk of birth defects for abacavir or lamivudine compared with the background rate for birth defects of 2.7% in the metropolitan atlanta congenital de

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teva pharmaceuticals usa, inc. - carbamazepine (unii: 33cm23913m) (carbamazepine - unii:33cm23913m) - carbamazepine 200 mg - epitol (carbamazepine tablets) is indicated for use as an anticonvulsant drug. evidence supporting efficacy of epitol (carbamazepine tablets) as an anticonvulsant was derived from active drug-controlled studies that enrolled patients with the following seizure types: - partial seizures with complex symptomatology (psychomotor, temporal lobe). patients with these seizures appear to show greater improvement than those with other types. - generalized tonic-clonic seizures (grand mal). - mixed seizure patterns which include the above, or other partial or generalized seizures. absence seizures (petit mal) do not appear to be controlled by epitol (carbamazepine tablets) (see precautions, general ). epitol (carbamazepine tablets) is indicated in the treatment of the pain associated with true trigeminal neuralgia. beneficial results have also been reported in glossopharyngeal neuralgia. this drug is not a simple analgesic and should not be used for the relief of trivial aches or pains. epitol should not be used in patients with a history of previous bone marrow depression, hypersensitivity to the drug, or known sensitivity to any of the tricyclic compounds, such as amitriptyline, desipramine, imipramine, protriptyline, nortriptyline, etc. likewise, on theoretical grounds its use with monoamine oxidase (mao) inhibitors is not recommended. before administration of epitol, mao inhibitors should be discontinued for a minimum of 14 days, or longer if the clinical situation permits. coadministration of carbamazepine and nefazodone may result in insufficient plasma concentrations of nefazodone and its active metabolite to achieve a therapeutic effect. coadministration of carbamazepine with nefazodone is contraindicated. no evidence of abuse potential has been associated with carbamazepine, nor is there evidence of psychological or physical dependence in humans.

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teva pharmaceuticals usa, inc. - aripiprazole (unii: 82vfr53i78) (aripiprazole - unii:82vfr53i78) - aripiprazole 2 mg - aripiprazole tablets are indicated for the treatment of: - schizophrenia [see clinical studies (14.1) ] additional pediatric use information is approved for otsuka america pharmaceutical, inc.’s abilify® (aripiprazole) product. however, due to otsuka america pharmaceutical, inc.’s marketing exclusivity rights, this drug product is not labeled with that information. aripiprazole is contraindicated in patients with a history of a hypersensitivity reaction to aripiprazole. reactions have ranged from pruritus/urticaria to anaphylaxis [see adverse reactions (6.2) ]. pregnancy category c pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to aripiprazole during pregnancy. for more information contact the national pregnancy registry for atypical antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/. risk summary neonates exposed to antipsychotic drugs (including aripiprazole) during t

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teva pharmaceuticals usa, inc. - raloxifene hydrochloride (unii: 4f86w47br6) (raloxifene - unii:yx9162eo3i) - raloxifene hydrochloride 60 mg - raloxifene hydrochloride tablets are indicated for the treatment and prevention of osteoporosis in postmenopausal women [see clinical studies (14.1, 14.2) ]. raloxifene hydrochloride tablets are indicated for the reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis [see clinical studies (14.3) ]. raloxifene hydrochloride tablets are indicated for the reduction in risk of invasive breast cancer in postmenopausal women at high risk of invasive breast cancer [see clinical studies (14.4) ]. the effect in the reduction in the incidence of breast cancer was shown in a study of postmenopausal women at high risk for breast cancer with a 5-year planned duration with a median follow-up of 4.3 years [see clinical studies (14.4) ]. twenty-seven percent of the participants received drug for 5 years. the long-term effects and the recommended length of treatment are not known. high risk of breast cancer is defined as at least one breast biopsy showing lobular carcinoma in situ (lcis) or atyp

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teva pharmaceuticals usa, inc. - fluticasone propionate (unii: o2gmz0lf5w) (fluticasone - unii:cut2w21n7u), salmeterol xinafoate (unii: 6ew8q962a5) (salmeterol - unii:2i4bc502bt) - fluticasone propionate 55 ug - fluticasone propionate/salmeterol multidose dry powder inhaler (fs mdpi) is indicated for the treatment of asthma in adult and pediatric patients aged 12 years and older. fluticasone propionate/salmeterol mdpi should be used for patients not adequately controlled on a long term asthma control medication such as an inhaled corticosteroid or whose disease warrants initiation of treatment with both an inhaled corticosteroid and long acting beta2 -adrenergic agonist (laba). limitations of use : fluticasone propionate/salmeterol mdpi is not indicated for the relief of acute bronchospasm. fluticasone propionate/salmeterol mdpi is contraindicated in: - the primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required [see warnings and precautions  (5.2)] . - patients with known severe hypersensitivity to milk proteins or who have demonstrated hypersensitivity to fluticasone propionate or any of the excipients [see warnings and precautions (5.10) and description (11)] . risk summary there are no randomized clinical studies of fluticasone propionate/salmeterol mdpi or individual monoproducts, fluticasone propionate and salmeterol, in pregnant women. there are clinical considerations with the use of fluticasone propionate/salmeterol mdpi in pregnant women [see clinical considerations] . animal reproduction studies are available with the combination of fluticasone propionate and salmeterol as well as individual components. in animals, teratogenicity characteristic of corticosteroids, decreased fetal body weight and/or skeletal variations, in rats, mice, and rabbits were observed with subcutaneously administered maternal toxic doses of fluticasone propionate less than the maximum recommended human daily inhaled dose (mrhdid) on a mcg/m2 basis [see data] . however, fluticasone propionate administered via inhalation to rats decreased fetal body weight, but did not induce teratogenicity at a maternal toxic dose less than the mrhdid on a mcg/m2 basis [see data] . experience with oral corticosteroids suggests that rodents are more prone to teratogenic effects from corticosteroids than humans. oral administration of salmeterol to pregnant rabbits caused teratogenicity characteristic of beta-adrenoceptor stimulation at maternal doses approximately 700 times the mrhdid on a mcg/m2 basis. these adverse effects generally occurred at large multiples of the mrhdid when salmeterol was administered by the oral route to achieve high systemic exposures. no such effects occurred at an oral salmeterol dose approximately 420 times the mrhdid [see data] . the estimated risk of major birth defects and miscarriage for the indicated population is unknown. in the u.s. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. clinical considerations disease‑associated maternal and/or embryo/fetal risk in women with poorly or moderately controlled asthma, there is an increased risk of several perinatal adverse outcomes such as preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. pregnant women with asthma should be closely monitored and medication adjusted as necessary to maintain optimal asthma control. data animal data fluticasone propionate and salmeterol:  in an embryo/fetal development study with pregnant rats that received the combination of subcutaneous administration of fluticasone propionate and oral administration of salmeterol at doses of 0/1000, 30/0, 10/100, 30/1000, and 100/10,000 mcg/kg/day (as fluticasone propionate/salmeterol) during the period of organogenesis, findings were generally consistent with the individual monoproducts and there was no exacerbation of expected fetal effects. omphalocele, increased embryo/fetal deaths, decreased body weight, and skeletal variations were observed in rat fetuses, in the presence of maternal toxicity, when combining fluticasone propionate at a dose approximately 2 times the mrhdid (on a mcg/m2 basis at a maternal subcutaneous dose of 100 mcg/kg/day) and a dose of salmeterol at approximately 3500 times the mrhdid (on a mcg/m2 basis at a maternal oral dose of 10,000 mcg/kg/day). the rat no observed adverse effect level (noael) was observed when combining fluticasone propionate at a dose 0.6 times the mrhdid (on a mcg/m2 basis at a maternal subcutaneous dose of 30 mcg/kg/day) and a dose of salmeterol at approximately 350 times the mrhdid (on a mcg/m2 basis at a maternal oral dose of 1000 mcg/kg/day). in an embryo/fetal development study with pregnant mice that received the combination of subcutaneous administration of fluticasone propionate and oral administration of salmeterol at doses of 0/1400, 40/0, 10/200, 40/1400, or 150/10,000 mcg/kg/day (as fluticasone propionate/salmeterol) during the period of organogenesis, findings were generally consistent with the individual monoproducts and there was no exacerbation of expected fetal effects. cleft palate, fetal death, increased implantation loss, and delayed ossification were observed in mouse fetuses when combining fluticasone propionate at a dose approximately 1.4 times the mrhdid (on a mcg/m2 basis at a maternal subcutaneous dose of 150 mcg/kg/day) and salmeterol at a dose approximately 1470 times the mrhdid (on a mcg/m2 basis at a maternal oral dose of 10,000 mcg/kg/day). no developmental toxicity was observed at combination doses of fluticasone propionate up to approximately 0.8 times the mrhdid (on a mcg/m2 basis at a maternal subcutaneous dose of 40 mcg/kg) and doses of salmeterol up to approximately 420 times the mrhdid (on a mcg/m2 basis at a maternal oral dose of 1400 mcg/kg). fluticasone propionate:   in embryo/fetal development studies with pregnant rats and mice dosed by the subcutaneous route throughout the period of organogenesis, fluticasone propionate was teratogenic in both species. omphalocele, decreased body weight, and skeletal variations were observed in rat fetuses, in the presence of maternal toxicity, at a dose approximately 2 times the mrhdid (on a mcg/m2 basis with a maternal subcutaneous dose of 100 mcg/kg/day). the rat noael was observed at approximately 0.6 times the mrhdid (on a mcg/m2 basis with a maternal subcutaneous dose of 30 mcg/kg/day). cleft palate and fetal skeletal variations were observed in mouse fetuses at a dose approximately 0.5 times the mrhdid (on a mcg/m2 basis with a maternal subcutaneous dose of 45 mcg/kg/day). the mouse noael was observed with a dose approximately 0.16 times the mrhdid (on a mcg/m2 basis with a maternal subcutaneous dose of 15 mcg/kg/day). in an embryo/fetal development study with pregnant rats dosed by the inhalation route throughout the period of organogenesis, fluticasone propionate produced decreased fetal body weights and skeletal variations, in the presence of maternal toxicity, at a dose approximately 0.5 times the mrhdid (on a mcg/m2 basis with a maternal inhalation dose of 25.7 mcg/kg/day); however, there was no evidence of teratogenicity. the noael was observed with a dose approximately 0.1 times the mrhdid (on a mcg/m2 basis with a maternal inhalation dose of 5.5 mcg/kg/day). in an embryo/fetal development study in pregnant rabbits that were dosed by the subcutaneous route throughout organogenesis, fluticasone propionate produced reductions of fetal body weights, in the presence of maternal toxicity at doses approximately 0.02 times the mrhdid and higher (on a mcg/m2 basis with a maternal subcutaneous dose of 0.57 mcg/kg/day). teratogenicity was evident based upon a finding of cleft palate for 1 fetus at a dose approximately 0.2 times the mrhdid (on a mcg/m2 basis with a maternal subcutaneous dose of 4 mcg/kg/day). the noael was observed in rabbit fetuses with a dose approximately 0.004 times the mrhdid (on a mcg/m2 basis with a maternal subcutaneous dose of 0.08 mcg/kg/day). in a pre- and post-natal development study in pregnant rats dosed by the subcutaneous route from late gestation through delivery and lactation (gestation day 17 to postpartum day 22), fluticasone propionate was not associated with decreases in pup body weight, and had no effects on developmental landmarks, learning, memory, reflexes, or fertility at doses up to approximate equivalence to the mrhdid (on a mcg/m2 basis with maternal subcutaneous doses up to 50 mcg/kg/day). fluticasone propionate crossed the placenta following subcutaneous administration to mice and rats and oral administration to rabbits. salmeterol: in three embryo/fetal development studies, pregnant rabbits received oral administration of salmeterol at doses ranging from 100 to 10,000 mcg/kg/day during the period of organogenesis. in pregnant dutch rabbits administered salmeterol doses approximately 700 times the mrhdid (on a mcg/m2 basis at maternal oral doses of 1000 mcg/kg/day and higher), fetal toxic effects were observed characteristically resulting from beta‑adrenoceptor stimulation. these included precocious eyelid openings, cleft palate, sternebral fusion, limb and paw flexures, and delayed ossification of the frontal cranial bones. no such effects occurred at a salmeterol dose approximately 420 times the mrhdid (on a mcg/m2 basis at a maternal oral dose of 600 mcg/kg/day). new zealand white rabbits were less sensitive since only delayed ossification of the frontal cranial bones was seen at a salmeterol dose approximately 7,000 times the mrhdid (on a mcg/m2 basis at a maternal oral dose of 10,000 mcg/kg/day). in two embryo/fetal development studies, pregnant rats received salmeterol by oral administration at doses ranging from 100 to 10,000 mcg/kg/day during the period of organogenesis. salmeterol produced no maternal toxicity or embryo/fetal effects at doses up to 3500 times the mrhdid (on a mcg/m2 basis at maternal oral doses up to 10,000 mcg/kg/day). in a peri-and post-natal development study in pregnant rats dosed by the oral route from late gestation through delivery and lactation, salmeterol at a dose 3500 times the mrhdid (on mcg/m2 basis with a maternal oral dose of 10,000 mcg/kg/day) was fetotoxic and decreased the fertility of survivors. salmeterol xinafoate crossed the placenta following oral administration to mice and rats. risk summary there are no available data on the presence of fluticasone propionate or salmeterol in human milk, the effects on the breastfed child, or the effects on milk production. other corticosteroids have been detected in human milk. however, fluticasone propionate and salmeterol concentrations in plasma after inhaled therapeutic doses are low and therefore concentrations in human breast milk are likely to be correspondingly low [see clinical pharmacology (12.3)] . the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for fluticasone propionate/salmeterol mdpi and any potential adverse effects on the breastfed child from fluticasone propionate/salmeterol mdpi or from the underlying maternal condition. data animal data subcutaneous administration of tritiated fluticasone propionate at a dose in lactating rats approximately 0.2 times the mrhdid for adults (on a mcg/m2 basis) resulted in measurable levels in milk.  oral administration of salmeterol at a dose in lactating rats approximately 2900 times the mrhdid for adults (on a mcg/m2 basis) resulted in measurable levels in milk. the safety and effectiveness of fluticasone propionate/salmeterol mdpi have been established for the treatment of asthma in pediatric patients aged 12 years and older whose asthma (1) is inadequately controlled on a long term asthma control medication or (2) warrants initiation of treatment with both an ics and a laba.  use of fluticasone propionate/salmeterol mdpi in pediatric patients aged 12 to 17 years for this indication is supported by evidence from two adequate and well-controlled trials in pediatric patients 12 years old and older with persistent symptomatic asthma despite ics or ics/laba therapy (trials 1 and 2) [see clinical studies (14)].  in these trials, 58 adolescents received fluticasone propionate/salmeterol mdpi one inhalation twice daily. the safety and effectiveness of fluticasone propionate/salmeterol mdpi have not been established in pediatric patients younger than 12 years of age for the treatment of asthma. effectiveness was not demonstrated in one adequate and well-controlled study conducted in 211 patients aged 4 to 11 years with persistent asthma on a stable asthma regimen who were treated with fluticasone propionate/salmeterol mdpi 55 mcg/14 mcg one inhalation twice daily. effect on growth inhaled corticosteroids, including fluticasone propionate, a component of this product, may cause a reduction in growth velocity in adolescents [see warning and precautions (5.13)] . the growth of pediatric patients receiving ics, including fluticasone propionate/salmeterol mdpi, should be monitored. if an adolescent on any corticosteroid appears to have growth suppression, the possibility that he/she is particularly sensitive to this effect of corticosteroids should be considered. in such patients, the potential growth effects of prolonged ics treatment should be weighed against the clinical benefits obtained. to minimize the systemic effects of ics, including fluticasone propionate/salmeterol mdpi, each patient should be titrated to the lowest strength that effectively controls his/her asthma [see dosage and administration (2)]. no overall differences in safety or effectiveness were observed in data collected in 54 subjects aged 65 years and older versus younger subjects who were treated with fluticasone propionate/salmeterol mdpi in placebo-controlled phase 2 and 3 asthma studies. formal pharmacokinetic studies using fluticasone propionate/salmeterol mdpi have not been conducted in patients with hepatic impairment. however, since both fluticasone propionate and salmeterol are predominantly cleared by hepatic metabolism [see clinical pharmacology (12.3)] , impairment of liver function may lead to accumulation of fluticasone propionate and salmeterol in plasma. therefore, patients with hepatic impairment should be closely monitored. formal pharmacokinetic studies using fluticasone propionate/salmeterol mdpi have not been conducted in patients with renal impairment. instructions for use fluticasone propionate and salmeterol inhalation powder 55 mcg/14 mcg fluticasone propionate and salmeterol inhalation powder 113 mcg/14 mcg fluticasone propionate and salmeterol inhalation powder 232 mcg/14 mcg for oral inhalation use   your fluticasone propionate/salmeterol inhalation powder inhaler when you are ready to use your inhaler for the first time, remove the inhaler from the foil pouch. there are 2 main parts of your inhaler including the: - white inhaler with the mouthpiece. see figure a. - yellow cap that covers the mouthpiece of the inhaler. see figure a. there is a dose counter in the back of the inhaler with a viewing window that shows you how many doses of medicine you have left. see figure a. figure a   - your inhaler contains 60 doses (inhalations). see figure b. - the dose counter shows the number of doses left in your inhaler. - when there are 20 doses left, the color of the numbers on the dose counter will change to red and you should refill your prescription or ask your healthcare provider for another prescription. - when the dose counter displays ‘0’ your inhaler is empty and you should stop using the inhaler and throw it away. see figure b. figure b important: - always close the cap after each inhalation so your inhaler will be ready for you to take your next dose . do not open the cap unless you are ready for your next dose. - you will hear a “click” sound when the cap is opened all the way. if you do not hear the “click” sound the inhaler may not be activated to give you a dose of medicine. - this inhaler does not have an activation button or medicine canister. when you open the cap, a dose of fluticasone propionate/salmeterol inhalation powder will be activated for delivery of the medicine. - do not use a spacer or volume holding chamber with the inhaler. this inhaler does not need priming. using your fluticasone propionate/salmeterol inhalation powder inhaler: important: make sure the cap is closed before you start using your inhaler. step 1. open - hold the inhaler upright and open the yellow cap all the way until it “clicks”. see figure c. - each time you open the yellow cap and it “clicks”, 1 dose of fluticasone propionate/salmeterol inhalation powder is ready to be inhaled.   figure c   remember: - for the correct use of your inhaler, hold it upright as you open the yellow cap. see figure d. - do not hold the inhaler in any other way as you open the yellow cap. - do not open the yellow cap until you are ready to take a dose of fluticasone propionate/salmeterol inhalation powder. figure d   step 2. inhale - before you inhale, breathe out (exhale) through your mouth and push as much air from your lungs as you can. see figure e. - do not exhale into the inhaler mouthpiece. figure e - put the mouthpiece in your mouth and close your lips tightly around it. see figure f.   figure f - do not block the vent above the mouthpiece with your lips or fingers. see figure g.   figure g   - breathe in quickly and deeply through your mouth to deliver the dose of medicine to your lungs. - remove the inhaler from your mouth. - hold your breath for about 10 seconds or for as long as you comfortably can. - your inhaler delivers your dose of medicine as a very fine powder that you may or may not taste or feel. do not take an extra dose from the inhaler even if you do not taste or feel the medicine.   step 3.  close figure h - close the yellow cap firmly over the mouthpiece. see figure h. - make sure you close the yellow cap after each inhalation so that the inhaler will be ready for your next dose. - rinse your mouth with water without swallowing after each inhalation.   how should i store the fluticasone propionate/salmeterol inhalation powder inhaler? - store your inhaler at room temperature between 59ºf and 77ºf (15ºc and 25ºc). - avoid exposure to extreme heat, cold, or humidity. - store your inhaler in the unopened foil pouch and only open when ready for use. - keep the yellow cap on the inhaler closed during storage. - keep your inhaler dry and clean at all times. - keep your inhaler and all medicines out of the reach of children.   cleaning your fluticasone propionate/salmeterol inhalation powder inhaler - do not wash or put any part of your inhaler in water. replace your inhaler if washed or placed in water. - your inhaler contains a powder and must be kept clean and dry at all times. - you can clean the mouthpiece if needed using a dry cloth or tissue. routine cleaning is not required.   replacing your fluticasone propionate/salmeterol inhalation powder inhaler - immediately replace your inhaler if the mouthpiece cover is damaged or broken. never take the inhaler apart. - the dose counter on the back of your inhaler shows how many doses you have left. - when there are 20 doses left, the color of the numbers on the dose counter will change to red and you should refill your prescription or ask your healthcare provider for another prescription. - when the counter displays ‘0’ your inhaler is empty and you should stop using the inhaler and throw it away. - throw away your inhaler 30 days after opening the foil pouch, when the dose counter displays ‘0’, or after the expiration date on the product, whichever comes first.   important information - do not open the yellow cap unless you are taking a dose. repeatedly opening and closing the cap without inhaling a dose will waste the medicine and may damage your inhaler. - your inhaler contains dry powder so it is important that you do not blow or breathe into it.   support - if you have any questions about your fluticasone propionate/salmeterol inhalation powder inhaler or how to use your inhaler, go to the reference branded product website at www.myairduo.com, or call 1-888-482-9522. these instructions for use have been approved by the u.s. food and drug administration. distributed by: teva pharmaceuticals usa, inc. parsippany, nj 07054 ©2021 teva respiratory, llc. all rights reserved. fpsifu-005 revised: july 2021

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hikma pharmaceuticals usa inc. - morphine sulfate (unii: x3p646a2j0) (morphine - unii:76i7g6d29c) - morphine sulfate 4 mg in 1 ml - morphine sulfate injection is indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.  limitations of use : because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration [see warnings and precautions (5.1)] , reserve morphine sulfate injection for use in patients for whom alternative treatment options [e.g., non-opioid analgesics or opioid combination products]: - have not been tolerated, or are not expected to be tolerated, - have not provided adequate analgesia or are not expected to provide adequate analgesia. morphine sulfate injection should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate. - significant respiratory depression [see warnings and precautions (5.2)] - acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see warnings and precautions (5.7)] - concurrent use of monoamine oxidase inhibitors (maois) or use of maois within the last 14 days [see warnings and precautions (5.8)]. - known or suspected gastrointestinal obstruction, including paralytic ileus [see warnings and precautions (5.12)] - hypersensitivity to morphine (e.g., anaphylaxis) [see adverse reactions (6)] risk summary use of opioid analgesics for an extended period of time during pregnancy can cause neonatal opioid withdrawal syndrome [see warnings and precautions (5.4)]. there are no available data with morphine sulfate injection in pregnant women to inform a drug-associated risk for major birth defects and miscarriage or adverse maternal outcomes. there are adverse outcomes reported with fetal exposure to opioid analgesics (see clinical considerations ). published studies with morphine use during pregnancy have not reported a clear association with morphine and major birth defects [see human data]. in published animal reproduction studies, morphine administered subcutaneously during the early gestational period produced neural tube defects (i.e., exencephaly and cranioschisis) at 5 and 16 times the human daily dose of 60 mg based on body surface area (hdd) in hamsters and mice, respectively, lower fetal body weight and increased incidence of abortion at 0.4 times the hdd in the rabbit, growth retardation at 6 times the hdd in the rat, and axial skeletal fusion and cryptorchidism at 16 times the hdd in the mouse. administration of morphine sulfate to pregnant rats during organogenesis and through lactation resulted in cyanosis, hypothermia, decreased brain weights, pup mortality, decreased pup body weights, and adverse effects on reproductive tissues at 3–4 times the hdd; and long-term neurochemical changes in the brain of offspring which correlate with altered behavioral responses that persist through adulthood at exposures comparable to and less than the hdd [see animal data] . based on animal data, advise pregnant women of the potential risk to a fetus. the estimated background risk of major birth defects and miscarriage for the indicated population is unknown. allpregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. clinical considerations   fetal/neonatal adverse reactions use of opioid analgesics for an extended period of time 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 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 signs of neonatal opioid withdrawal syndrome and manage accordingly [see warnings and precautions (5.4)] . labor or delivery 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. morphine sulfate injection is not recommended for use in women during and immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate. opioid analgesics, including morphine sulfate injection, 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. data human data the results from a population-based prospective cohort, including 70 women exposed to morphine during the first trimester of pregnancy and 448 women exposed to morphine at any time during pregnancy, indicate no increased risk for congenital malformations. however, these studies cannot definitely establish the absence of any risk because of methodological limitations, including small sample size and non- randomized study design. animal data formal reproductive and developmental toxicology studies for morphine have not been conducted. exposure margins for the following published study reports are based on human daily dose of 60 mg morphine using a body surface area comparison (hdd). neural tube defects (exencephaly and cranioschisis) were noted following subcutaneous administration of morphine sulfate (35–322 mg/kg) on gestation day 8 to pregnant hamsters (4.7 to 43.5 times the hdd). a no adverse effect level was not defined in this study and the findings cannot be clearly attributed to maternal toxicity. neural tube defects (exencephaly), axial skeletal fusions, and cryptorchidism were reported following a single subcutaneous (sc) injection of morphine sulfate to pregnant mice (100–500 mg/kg) on gestation day 8 or 9 at 200 mg/kg or greater (16 times the hdd) and fetal resorption at 400 mg/kg or higher (32 times the hdd). no adverse effects were noted following 100 mg/kg morphine in this model (8 times the hdd). in one study, following continuous subcutaneous infusion of doses greater than or equal to 2.72 mg/kg to mice (0.2 times the hdd), exencephaly, hydronephrosis, intestinal hemorrhage, split supraoccipital, malformed sternebrae, and malformed xiphoid were noted. the effects were reduced with increasing daily dose; possibly due to rapid induction of tolerance under these infusion conditions. the clinical significance of this report is not clear. decreased fetal weights were observed in pregnant rats treated with 20 mg/kg/day morphine sulfate (3.2 times the hdd) from gestation day 7 to 9. there was no evidence of malformations despite maternal toxicity (10% mortality). in a second rat study, decreased fetal weight and increased incidences of growth retardation were noted at 35 mg/kg/day (5.7 times the hdd) and there was a reduced number of fetuses at 70 mg/kg/day (11.4 times the hdd) when pregnant rats were treated with 10, 35, or 70 mg/kg/day morphine sulfate via continuous infusion from gestation day 5 to 20. there was no evidence of fetal malformations or maternal toxicity. an increased incidence of abortion was noted in a study in which pregnant rabbits were treated with 2.5 (0.8 times the hdd) to 10 mg/kg morphine sulfate via subcutaneous injection from gestation day 6 to 10. in a second study, decreased fetal body weights were reported following treatment of pregnant rabbits with increasing doses of morphine (10–50 mg/kg/day) during the pre-mating period and 50 mg/kg/day (16 times the hdd) throughout the gestation period. no overt malformations were reported in either publication; although only limited endpoints were evaluated. in published studies in rats, exposure to morphine during gestation and/or lactation periods is associated with: decreased pup viability at 12.5 mg/kg/day or greater (2 times the hdd); decreased pup body weights at 15 mg/kg/day or greater (2.4 times the hdd); decreased litter size, decreased absolute brain and cerebellar weights, cyanosis, and hypothermia at 20 mg/kg/day (3.2 times the hdd); alteration of behavioral responses (play, social-interaction) at 1 mg/kg/day or greater (0.2 times the hdd); alteration of maternal behaviors (e.g., decreased nursing and pup retrievals) in mice at 1 mg/kg or higher (0.08 times the hdd) and rats at 1.5 mg/kg/day or higher (0.2 times the hdd); and a host of behavioral abnormalities in the offspring of rats, including altered responsiveness to opioids at 4 mg/kg/day (0.7 times the hdd) or greater. fetal and/or postnatal exposure to morphine in mice and rats has been shown to result in morphological changes in fetal and neonatal brain and neuronal cellloss, alteration of a number of neurotransmitter and neuromodulator systems, including opioid and non- opioid systems, and impairment in various learning and memory tests that appear to persist into adulthood. these studies were conducted with morphine treatment usually in the range of 4 to 20 mg/kg/day (0.7 to 3.2 times the hdd). additionally, delayed sexual maturation and decreased sexual behaviors in female offspring at 20 mg/kg/day (3.2 times the hdd), and decreased plasma and testicular levels of luteinizing hormone and testosterone, decreased testes weights, seminiferous tubule shrinkage, germinal cell aplasia, and decreased spermatogenesis in male offspring were also observed at 20 mg/kg/day (3.2 times the hdd). decreased litter size and viability were observed in the offspring of male rats that were intraperitoneally administered morphine sulfate for 1 day prior to mating at 25 mg/kg/day (4.1 times the hdd) and mated to untreated females. decreased viability and body weight and/or movement deficits in both first and second generation offspring were reported when male mice were treated for 5 days with escalating doses of 120 to 240 mg/kg/day morphine sulfate (9.7 to 19.5 times the hdd) or when female mice treated with escalating doses of 60 to 240 mg/kg/day (4.9 to 19.5 times the hdd) followed by a 5- day treatment-free recovery period prior to mating. similar multigenerational findings were also seen in female rats pre-gestationally treated with escalating doses of 10 to 22 mg/kg/day morphine (1.6 to 3.6 times the hdd). risk summary morphine is present in breast milk. published lactation studies report variable concentrations of morphine in breast milk with administration of immediate-release morphine to nursing mothers in the early postpartum period with a milk-to-plasma morphine auc ratio of 2.5:1 measured in one lactation study. however, there is insufficient information to determine the effects of morphine on the breastfed infant and the effects of morphine on milk production. lactation studies have not been conducted with morphine sulfate injection, and no information is available on the effects of the drug on the breastfed infant or the effects of the drug on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for morphine sulfate injection, and any potential adverse effects on the breastfed infant from morphine sulfate injection, or from the underlying maternal condition. clinical considerations monitor infants exposed to morphine sulfate injection, through breast milk for excess sedation and respiratory depression. withdrawal symptoms can occur in breastfed infants when maternal administration of morphine is stopped, or when breastfeeding is stopped. infertility use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. it is not known whether these effects on fertility are reversible [see clinical pharmacology (12.2)]. in published animal studies, morphine administration adversely effected fertility and reproductive endpoints in male rats and prolonged estrus cycle in female rats [see nonclinical toxicology (13)] . the safety and effectiveness of morphine sulfate injection in pediatric patients below the age of 18 have not been established. the pharmacodynamic effects of morphine in the elderly are more variable than in the younger population. older patients will vary widely in the effective initial dose, rate of development of tolerance and the frequency and magnitude of associated adverse effects as the dose is increased. initial elderly patients (aged 65 years or older) may have increased sensitivity to morphine. 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. 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 morphine sulfate injection slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see warnings and precautions (5.7)] . morphine 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. morphine pharmacokinetics have been reported to be significantly altered in patients with cirrhosis. start these patients with a lower than normal dosage of morphine sulfate injection and titrate slowly while monitoring for signs of respiratory depression, sedation, and hypotension [see clinical pharmacology (12.3)]. morphine pharmacokinetics are altered in patients with renal failure. start these patients with a lower than normal dosage of morphine sulfate injection and titrate slowly while monitoring for signs of respiratory depression, sedation, and hypotension [see clinical pharmacology (12.3)]. morphine sulfate injection contains morphine., a schedule ii controlled substance. morphine sulfate injection contains morphine, a substance with a high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see warnings and precautions (5.1)] . misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed. abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than to other activities and obligations), and possible tolerance or physical dependence. misuse and abuse of morphine sulfate injection increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. the risk is increased with concurrent abuse of morphine sulfate injection with alcohol and/or other cns depressants. abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. in addition, abuse of opioids can occur in the absence of addiction. all patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. patients at high risk of morphine sulfate injection abuse include those with a history of prolonged use of any opioid, including products containing morphine, those with a history of drug or alcohol abuse, or those who use morphine sulfate injection in combination with other abused drugs. “drug-seeking” behavior is very common in persons with substance use disorders. 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 provider(s). “doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control. morphine sulfate injection, 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 reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. risks specific to abuse of morphine sulfate injection abuse of morphine sulfate injection poses a risk of overdose and death. the risk is increased with concurrent use of morphine sulfate injection with alcohol and/or other cns depressants. parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and hiv. both tolerance and physical dependence can develop during use of opioid therapy. tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use. morphine sulfate injection should not be abruptly discontinued in a physically-dependent patient [see dosage and administration 2.4]. if morphine sulfate injection is abruptly discontinued in a physically-dependent patient, a withdrawal syndrome may occur. some or allof the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, perspiration, chills, myalgia, and mydriasis. other signs and symptoms also may develop, including, irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. infants born to mothers physically-dependent on opioids will also be physically-dependent and may exhibit respiratory difficulties and withdrawal signs [see use in specific populations (8.1)].

United States - English - NLM (National Library of Medicine)

hikma pharmaceuticals usa inc. - morphine sulfate (unii: x3p646a2j0) (morphine - unii:76i7g6d29c) - morphine sulfate 15 mg - morphine sulfate tablets are indicated for the management of: limitations of use : because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration, [see warnings and precautions (5.1)] , reserve morphine sulfate tablets for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or opioid combination products): morphine sulfate tablets should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadeq uate. morphine sulfate tablets are contraindicated in patients with: risk summary: use of opioid analgesics for an extended period of time during pregnancy can cause neonatal opioid withdrawal syndrome [see warnings and precautions (5.4)]. there are no available data with morphine sulfate tablets in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. published studies with morphine use during pregnancy have not reported a clear association with morphine and major birth defects [see human data]. in published animal reproduction studies, morphine administered subcutaneously during the early gestational period produced neural tube defects (i.e., exencephaly and cranioschisis) at 5 and 16 times the human daily dose of 60 mg based on body surface area (hdd) in hamsters and mice, respectively, lower fetal body weight and increased incidence of abortion at 0.4 times the hdd in the rabbit, growth retardation at 6 times the hdd in the rat, and axial skeletal fusion and cryptorchidism at 16 times the hdd in the mouse. administration of morphine sulfate to pregnant rats during organogenesis and through lactation resulted in cyanosis, hypothermia, decreased brain weights, pup mortality, decreased pup body weights, and adverse effects on reproductive tissues at 3 to 4 times the hdd; and long-term neurochemical changes in the brain of offspring which correlate with altered behavioral responses that persist through adulthood at exposures comparable to and less than the hdd [see animal data] . based on animal data, advise pregnant women of the potential risk to a fetus. the 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. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. clinical considerations: fetal/neonatal adverse reactions: use of opioid analgesics for an extended period of time 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 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 signs of neonatal opioid withdrawal syndrome and manage accordingly [see warnings and precautions (5.4)] . labor or delivery: 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. morphine sulfate tablets are not recommended for use in women during and immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate. opioid analgesics, including morphine sulfate tablets, 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. data: human data: the results from a population-based prospective cohort, including 70 women exposed to morphine during the first trimester of pregnancy and 448 women exposed to morphine at any time during pregnancy, indicate no increased risk for congenital malformations. however, these studies cannot definitely establish the absence of any risk because of methodological limitations, including small sample size and non-randomized study design. animal data: formal reproductive and developmental toxicology studies for morphine have not been conducted. exposure margins for the following published study reports are based on human daily dose of 60 mg morphine using a body surface area comparison (hdd). neural tube defects (exencephaly and cranioschisis) were noted following subcutaneous administration of morphine sulfate (35 to 322 mg/kg) on gestation day 8 to pregnant hamsters (4.7 to 43.5 times the hdd). a no adverse effect level was not defined in this study and the findings cannot be clearly attributed to maternal toxicity. neural tube defects (exencephaly), axial skeletal fusions, and cryptorchidism were reported following a single subcutaneous (sc) injection of morphine sulfate to pregnant mice (100 to 500 mg/kg) on gestation day 8 or 9 at 200 mg/kg or greater (16 times the hdd) and fetal resorption at 400 mg/kg or higher (32 times the hdd). no adverse effects were noted following 100 mg/kg morphine in this model (8 times the hdd). in one study, following continuous subcutaneous infusion of doses greater than or equal to 2.72 mg/kg to mice (0.2 times the hdd), exencephaly, hydronephrosis, intestinal hemorrhage, split supraoccipital, malformed sternebrae, and malformed xiphoid were noted. the effects were reduced with increasing daily dose; possibly due to rapid induction of tolerance under these infusion conditions. the clinical significance of this report is not clear. decreased fetal weights were observed in pregnant rats treated with 20 mg/kg/day morphine sulfate (3.2 times the hdd) from gestation day 7 to 9. there was no evidence of malformations despite maternal toxicity (10% mortality). in a second rat study, decreased fetal weight and increased incidences of growth retardation were noted at 35 mg/kg/day (5.7 times the hdd) and there was a reduced number of fetuses at 70 mg/kg/day (11.4 times the hdd) when pregnant rats were treated with 10, 35, or 70 mg/kg/day morphine sulfate via continuous infusion from gestation day 5 to 20. there was no evidence of fetal malformations or maternal toxicity. an increased incidence of abortion was noted in a study in which pregnant rabbits were treated with 2.5 (0.8 times the hdd) to 10 mg/kg morphine sulfate via subcutaneous injection from gestation day 6 to 10. in a second study, decreased fetal body weights were reported following treatment of pregnant rabbits with increasing doses of morphine (10 to 50 mg/kg/day) during the pre-mating period and 50 mg/kg/day (16 times the hdd) throughout the gestation period. no overt malformations were reported in either publication; although only limited endpoints were evaluated. in published studies in rats, exposure to morphine during gestation and/or lactation periods is associated with: decreased pup viability at 12.5 mg/kg/day or greater (2 times the hdd); decreased pup body weights at 15 mg/kg/day or greater (2.4 times the hdd); decreased litter size, decreased absolute brain and cerebellar weights, cyanosis, and hypothermia at 20 mg/kg/day (3.2 times the hdd); alteration of behavioral responses (play, social-interaction) at 1 mg/kg/day or greater (0.2 times the hdd); alteration of maternal behaviors (e.g., decreased nursing and pup retrievals) in mice at 1 mg/kg or higher (0.08 times the hdd) and rats at 1.5 mg/kg/day or higher (0.2 times the hdd); and a host of behavioral abnormalities in the offspring of rats, including altered responsiveness to opioids at 4 mg/kg/day (0.7 times the hdd) or greater. fetal and/or postnatal exposure to morphine in mice and rats has been shown to result in morphological changes in fetal and neonatal brain and neuronal cell loss, alteration of a number of neurotransmitter and neuromodulator systems, including opioid and non-opioid systems, and impairment in various learning and memory tests that appear to persist into adulthood. these studies were conducted with morphine treatment usually in the range of 4 to 20 mg/kg/day (0.7 to 3.2 times the hdd). additionally, delayed sexual maturation and decreased sexual behaviors in female offspring at 20 mg/kg/day (3.2 times the hdd), and decreased plasma and testicular levels of luteinizing hormone and testosterone, decreased testes weights, seminiferous tubule shrinkage, germinal cell aplasia, and decreased spermatogenesis in male offspring were also observed at 20 mg/kg/day (3.2 times the hdd). decreased litter size and viability were observed in the offspring of male rats that were intraperitoneally administered morphine sulfate for 1 day prior to mating at 25 mg/kg/day (4.1 times the hdd) and mated to untreated females. decreased viability and body weight and/or movement deficits in both first and second generation offspring were reported when male mice were treated for 5 days with escalating doses of 120 to 240 mg/kg/day morphine sulfate (9.7 to 19.5 times the hdd) or when female mice treated with escalating doses of 60 to 240 mg/kg/day (4.9 to 19.5 times the hdd) followed by a 5-day treatment-free recovery period prior to mating. similar multigenerational findings were also seen in female rats pre-gestationally treated with escalating doses of 10 to 22 mg/kg/day morphine (1.6 to 3.6 times the hdd). risk summary: morphine is present in breast milk. published lactation studies report variable concentrations of morphine in breast milk with administration of immediate-release morphine to nursing mothers in the early postpartum period with a milk-to-plasma morphine auc ratio of 2.5:1 measured in one lactation study. however, there is insufficient information to determine the effects of morphine on the breastfed infant and the effects of morphine on milk production. lactation studies have not been conducted with morphine sulfate tablets and no information is available on the effects of the drug on the breastfed infant or the effects of the drug on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for morphine sulfate tablets and any potential adverse effects on the breastfed infant from morphine sulfate tablets or from the underlying maternal condition. clinical considerations: monitor infants exposed to morphine sulfate tablets through breast milk for excess sedation and respiratory depression. withdrawal symptoms can occur in breastfed infants when maternal administration of morphine is stopped, or when breastfeeding is stopped. infertility: use of opioids for an extended period of time 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) and clinical pharmacology (12.2)] . in published animal studies, morphine administration adversely effected fertility and reproductive endpoints in male rats and prolonged estrus cycle in female rats [see nonclinical toxicology (13)]. the safety and effectiveness of morphine sulfate tablets have been established for the management of pediatric patients weighing at least 50 kg with acute pain severe enough to require an opioid analgesic when alternative treatments are inadequate. use of morphine sulfate tablets in this age group is supported by clinical evidence in adults and supportive data from an open-label, safety and pharmacokinetic study in pediatric patients 2 through 17 years of age with post-operative acute pain. patients were excluded if they had used opioids for more than 7 days within the previous 30 days prior to surgery or had received opioids in any form in the previous 7 days prior to surgery.  initial dosing was approximately 0.15 mg/kg to 0.3 mg/kg.  pharmacokinetic modeling and simulation indicate that an initial dose of 15 mg morphine sulfate tablets to pediatric patients weighing at least 50 kg is expected to produce a maximum systemic exposure (cmax ) similar to that achieved after single dose administration of 10 mg morphine sulfate oral solution to adults [see clinical pharmacology (12.3)] . safety data were available in 81 patients who received single and multiple doses (63 patients aged 2 to 17 years received the oral solution; 18 patients aged 12 years to 17 years received the tablets). the median duration of treatment was 20 hours (range 4 hours to 36 hours). opioid and non-opioid rescue analgesics were allowed. the safety profile in pediatric patients consisted primarily of opioid-related adverse reactions and is similar to that observed in adults [see adverse reactions (6)]. the safety and effectiveness of morphine sulfate tablets have not been established for the management of pediatric patients weighing less than 50 kg with acute pain severe enough to require an opioid analgesic when alternative treatments are inadequate because the recommended dosage cannot be achieved with available tablet strengths. consider use of another morphine sulfate product in patients who cannot swallow oral tablets or who weigh less than 50 kg [see dosage and administration (2.3)] . the safety and effectiveness of morphine sulfate tablets have not been established for the management of pediatric patients with chronic pain severe enough to require an opioid analgesic when alternative treatments are inadequate. elderly patients (aged 65 years or older) may have increased sensitivity to morphine. in general, use caution when selecting a dose 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. 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 morphine sulfate tablets slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see warnings and precautions (5.7)] . morphine 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 regularly evaluate renal function. morphine pharmacokinetics have been reported to be significantly altered in patients with cirrhosis. start these patients with a lower than usual dosage of morphine sulfate tablets and titrate slowly while regularly evaluating for signs of respiratory depression, sedation, and hypotension [see clinical pharmacology (12.3)]. morphine sulfate pharmacokinetics are altered in patients with renal failure. start these patients with a lower than usual dosage of morphine sulfate tablets and titrate slowly while regularly evaluating for signs of respiratory depression, sedation, and hypotension [see clinical pharmacology (12.3)]. morphine sulfate tablets contain morphine, a schedule ii controlled substance. morphine sulfate tablets contains morphine, a substance with high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see warnings and precautions (5.1)]. misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed. abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. misuse and abuse of morphine sulfate tablets increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. the risk is increased with concurrent abuse of morphine sulfate tablets with alcohol and other cns depressants. abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. in addition, abuse of opioids can occur in the absence of addiction. all patients treated with opioids require careful and frequent re-evaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. patients at high risk of morphine sulfate tablets abuse include those with a history of prolonged use of any opioid, including products containing morphine, those with a history of drug or alcohol abuse, or those who use morphine sulfate tablets in combination with other abused drugs. “drug-seeking” behavior is very common in persons with substance use disorders. 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 provider(s). “doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control. morphine sulfate tablets, like other opioids, can be diverted for nonmedical 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 reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. risks specific to abuse of morphine sulfate tablets abuse of morphine sulfate tablets poses a risk of overdose and death. the risk is increased with concurrent use of morphine sulfate tablets with alcohol and/or other cns depressants. morphine sulfate tablets are approved for oral use only. parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and hiv. both tolerance and physical dependence can develop during use of opioid therapy. tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use. do not abruptly discontinue morphine sulfate tablets in a patient physically dependent on opioids. rapid tapering of morphine sulfate tablets in a patient physically dependent on opioids may lead to serious withdrawal symptoms, uncontrolled pain, and suicide. rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. when discontinuing morphine sulfate tablets gradually taper the dosage using a patient-specific plan that considers the following: the dose of morphine sulfate tablets the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. to improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. in patients taking opioids for an extended period of time at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see dosage and administration (2.5), and warnings and precautions (5.14)]. infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see use in specific populations (8.1)].