By J. Rune. Montana State University-Billings.

Where the estimated curve is assumed to be linear for Long-term Studies based on 24 months of real-time data and the lower spec- A stability protocol should describe not only how the ification limit is assumed to be 90% of label claim generic avana 100mg on-line, an stability study is to be designed and carried out but also expiration dating period of 24 months could be granted order discount avana on-line. When analyzing an attribute that is expected to increase This section describes an acceptable statistical approach with time buy cheap avana 50 mg online, the 95% one-sided upper confidence limit for to the analysis of stability data and the specific features the mean is recommended discount 100 mg avana with visa. In When analyzing an attribute with both an upper and general, an expiration dating or retest period should be a lower specification limit, special cases may lead to appli- determined on the basis of statistical analysis of observed cation of a two-sided 95% confidence limit. Limited extrapolation of the real-time data although chemical degradation of the active ingredient in beyond the observed range to extend the expiration dating a solution product would cause a decrease in the assayed or retest period at approval time may be considered if it concentration, evaporation of the solvent in the product is supported by the statistical analysis of real-time data, (through the container and closure) would result in an satisfactory accelerated data, and other nonprimary stabil- increase in the concentration. If both mechanisms were acting, establish with a high degree of confidence an expiration the concentration might decrease initially and then dating period during which average drug product attributes increase. In this case, the degradation pattern would not such as assay and degradation products of the batch will be linear, and more complicated statistical approaches remain within specifications. If the approach presented in this should be applicable to all future batches produced by the section is used, average parameters such as assay and same manufacturing process for the drug product. In this setting, testing of individual units, sects the appropriate specification limit. The a priori correctness of the assumed described above, such as the assumption that the variability pattern of change as a function of time is crucial in the case of the individual units from the batch average remains con- of extrapolation beyond the observed range. When estimat- stant over the several sampling times, are well known and ing a line or curve of change within the observed range of have been discussed in numerous statistical texts. The above data, the data themselves provide a check on the correctness procedures will remain valid even when these assumptions of the assumed relationship, and statistical methods may are violated to some degree. If severe violation of the be applied to test the goodness of fit of the data to the line assumptions in the data is noted, an alternate approach may or curve. No such internal check is available beyond the be necessary to accomplish the objective of determining an range of observed data. For example, if it has been assumed expiration dating period with a high degree of confidence. Expiration Dating Period for All Batches range of the observed data, the true curve is close enough to a straight line that no serious error is made by approxi- If batch-to-batch variability is small, that is, the relation- mating the relationship as a straight line. However, beyond ship between the parameter of interest such as assay or the observed data points, the true curve may diverge from degradation products and time is essentially the same from a straight line enough to have a significant effect on the batch to batch, stability data should be combined into one estimated expiration dating period. Combining the data should be supported For extrapolation beyond the observed range to be by preliminary testing of batch similarity. The similarity valid, the assumed change must continue to apply through of the estimated curves among the batches tested should the estimated expiration dating period. Thus, an expiration be assessed by applying statistical tests of the equality of dating period granted on the basis of extrapolation should slopes and of zero time intercepts. The level of signifi- always be verified by actual stability data as soon as these cance of the tests, expressed in the P value, should be data become available. Computation of Expiration Date equality of intercepts do not result in rejection at a level of significance of. The data generated in If the preliminary statistical test rejects the hypothesis support of the assigned expiration dating period should be of batch similarity because of unequal initial intercept val- from long-term studies under the storage conditions rec- ues, it may still be possible to establish that the lines are ommended in the labeling. If so, the data may only a month and year, the product should meet specifi- be combined for the purpose of estimating the common cations through the last day of the month. E, the initial values and the common slope using appropriate should support at least a 1-year expiration dating period. If data from several batches are Exceptions do exist, for example, with short half-life combined, as many batches as feasible should be combined radioactive drug products. Extension of Expiration Dating Period expiration dating period will depend on the minimum time An extension of the expiration dating period based on full a batch may be expected to remain within acceptable limits. The expiration dating period may be extended The statistical methods for determining an expiration dating in an annual report only if the criteria set forth in the period beyond the observed range of time points are the approved stability protocol are met in obtaining and ana- same as for determining an expiration dating period within lyzing data, including statistical analysis if appropriate. To approval, it is feasible to extend the tentative expiration extend the retest period, full long-term data from a formal dating period based on full long-term data obtained from stability study on three production batches using a proto- these batches in accordance with the approved protocol, col approved in an application or found acceptable in a including statistical analysis if appropriate, through a Prior drug master file should be provided. However, the expiration dating Similar to the extension of an expiration dating period period thus derived remains tentative until confirmed with for a drug product, a retest period for a drug substance full long-term data from at least three production batches. This can be achieved through an annual a Prior Approval Supplement before the change is made, report based on full long-term stability data (i. If the data are obtained under a a drug substance, it may be inappropriate to use a retest new or revised stability protocol, a Prior Approval Sup- date. Shortening of Expiration Dating Period When warranted, a previously approved expiration dating period may be shortened via a Changes Being Effected 3. The Intermediates supplemental application should provide pertinent infor- Intermediates such as blends, triturates, cores, extended- mation and the data that led to the shortening of the expi- release beads, or pellets may be held for up to 30 days ration dating period. The expiration dating period should from their date of production without being retested before be shortened to the nearest available real-time long-term use. An intermediate that is held for longer than 30 days test point where the product meets acceptance criteria. The should be monitored for stability under controlled, long- expiration dating period thus derived should be applied to term storage conditions for the length of the holding all subsequent production batches and may not be extended period. In addition, the first production batch of the fin- until the cause for the shortening is fully investigated, the ished drug product manufactured with such an intermedi- problem is resolved, and satisfactory stability data become ate should be monitored on long-term stability. When pre- available on at least three new production batches to cover vious testing of an intermediate or the related drug product the desired expiration dating period and are submitted in batches indicates that an intermediate may not be stable a Changes Being Effected Supplement. The frequency of testing of an intermediate’s stability A retest period for a drug substance may be established on is related to the length of the holding time. Where prac- the basis of the available data from long-term stability tical, testing should be done at a minimum of three time studies and, as such, can be longer than 24 months if sup- points after the initial testing of an intermediate. A retest date should be placed on the storage minimum, all critical parameters should be evaluated at container and on the shipping container for a bulk drug release of an intermediate and immediately before its use substance. A drug substance batch may be used without in the manufacture of the finished drug product. However, beyond In the event that the holding time for an intermediate the approved retest period, any remaining portion of the has not been qualified by appropriate stability evaluations, batch should be retested immediately before use. Retest of the expiration date assigned to the related finished drug different portions of the same batch for use at different product batch should be computed from the quality control times as needed is acceptable, provided that the batch has release date of the intermediate if this date does not exceed been stored under the defined conditions, the test methods 30 days from the date of production of the intermediate. The purpose 30 days from the date that the intermediate is introduced of retest is to qualify a specific batch of a drug substance into the manufacture of the finished drug product. General weight of the dosage unit remains constant, bracketing The use of reduced stability testing, such as a bracketing may not be applicable unless justified. Such justification design, may be a suitable alternative to a full testing pro- may include a demonstration of comparable stability pro- gram where the drug is available in multiple sizes or file among the different strengths based on data obtained strengths. This section discusses the types of products and from clinical and development batches, primary stability submissions to which a bracketing design is applicable batches, or production batches in support of primary sta- and the types of factors that can be bracketed. With this approach, the formulations should be identical or very closely related, and the container and closure system 2. Applicability should be the same between the supportive batches and The factors that may be bracketed in a stability study are the batches for which the bracketing design is intended. If the formulation is significantly different among the The types of drug products and the types of submissions to different strengths (e. Types of Drug Product Because of the complexity in product formulation, Bracketing design is applicable to most types of drug applicants are advised to consult the appropriate chemistry products, including immediate- and modified-release oral review team in advance when questions arise in the above solids, liquids, semisolids, and injectables. In the case in which the strength and the container delivery systems, may not be amenable to, or may need or fill size of a drug product both vary, bracketing design additional justification for, bracketing design. Types of Submissions Where a range of container fill sizes for a drug product A bracketing design may be used for primary stability of the same strength is to be evaluated, bracketing design batches in an original application, postapproval commit- may be applicable if the material and composition of the ment batches, annual batches, or batches intended to sup- container and the type of closure are the same throughout port supplemental changes. Such justification should demonstrate that the batches, commitment batches, or production batches. Bracketing protocols to be applied to postap- in the same container and closure (with identical material proval commitment batches and annual batches, if pro- and size) is to be tested, bracketing design may be appli- posed, will be approved as part of the original application. If the weights of a common granulation, or a capsule range made new bracketing design is used to generate stability data to by filling different plug fill weights of the same compo- support two different chemistry, manufacturing, or controls sition into different-size capsule shells. The phrase “very changes, the two proposed changes could be combined into closely related formulation” means a range of strengths one Prior Approval Supplement even though the latter may with a similar, but not identical, basic composition such otherwise qualify for a Changes Being Effected Supplement that the ratio of active ingredient to excipients remains or annual report under 314.

In pregnancy gastric emptying is also delayed buy avana 50 mg mastercard, while some drugs may increase or decrease gastric emptying and afect absorpton of other drugs 50mg avana otc. Hence variaton in plasma albumin levels order generic avana canada, fat content or muscle mass may all contribute to dose variaton order avana from india. With very highly albumin bound drugs like warfarin, a small change of albumin concen- traton can produce a big change in free medicine concen- traton and a dramatc change in therapeutc acton of a medicine. Metabolism Medicine metabolic rates are determined both by genetc and environmental factors. Medicine acetylaton shows genetc polymorphism, whereby individuals fall clearly into either fast or slow acetylator types. Medicine oxidaton, however, is poly- genic, and although a small proporton of the populaton can be classifed as very slow oxidizers of some drugs, for most drugs and most subjects there is a normal distributon of medicine metabolizing capacity, and much of the variaton is under envi- ronmental control. Renal disease or compettve tubular secreton of drugs can therefore slow down the excreton of certain drugs. Pharmacodynamic Variables There is signifcant variaton in receptor response to some drugs, especially central nervous system responses, for example pain and sedaton. Some of this is genetc, some due to tolerance, some due to interactons with other drugs and some due to addicton, for example, morphine and alcohol. Disease Variables Both liver and kidney disease can have major efects on medicine response, chiefy by the efect on metabolism and eliminaton respectvely (increasing toxicity), but also by their efect on plasma albumin (increased free medicine also increasing toxicity). Heart failure can also afect metabolism of drugs with rapid hepatc clearance (for example lidocaine, propranolol). Environmental pollut- ants, carcinogens, tobacco smoke, alcohol, anaesthetc drugs and pestcides can also induce metabolism. For example, in infantle malnutriton and in malnourished elderly populatons medicine oxidaton rates are decreased, while high protein diets, charcoal cooked foods and certain other foods act as metabolizing enzyme inducers. Sedatve and hypnotcs induce sleep beter in calm environment and when administered at night. Pharmacogenetc variaton will afect the medicine response, by 4-6 fold among diferent individuals. All major determinants of medicine response such as transporters, metabolizing enzymes, and receptors are controlled genetcally. These factors in certain cases may result in toxicity- for example toxicity caused by inhibi- tory efect of isoniazid on phenytoin metabolism seems to be more signifcant in slow acetylators of isoniazid than in those patents who metabolize the drug more rapidly. The Appendix 10 summarizes the pharmacogenetc variaton, the frequency of occurrence, drugs involved and the outcome. Unfortunately this is very ofen not the case, and physicians overlook one of the most important reasons for treatment failure that is poor adherence (compliance) with the treatment plan. The medicine may be poorly tolerated, may cause obvious adverse efects or may be prescribed in a toxic dose. Failure to adhere with such a prescripton has been described as ‘intelligent non-compliance’. Bad prescribing or a dispensing error may also create a problem, and regarding which patents may have neither the insight nor the courage to queston. Factors may be related to the patent, the disease, the doctor, the prescripton, the pharmacist or the health system and can ofen be avoided. Low-cost strategies for improving adherence increase efectveness of health interventons and reduce costs. Health care providers should be familiar with techniques for improving adherence and they should employ systems to assess adherence and to determine what infuences it. Patent Reasons In general, women tend to be more adherent than men, younger patents and the very elderly are less adherent, and people living alone are less adherent than those with partners or spouses. Patent disadvantages such as illiteracy, poor eyesight or cultural attudes (for example preference for traditonal or alternatve drugs and suspicion of modern medicine) may be very important in some individuals or societes, as may economic factors. Doctors should be aware that in most setngs less than half of patents initated on anthypertensive medicine treatment are stll taking it a year later. Similarly, in epilepsy, where events may occur at long intervals, adherence is notoriously unsatsfactory. The Doctor-Patent Interacton There is considerable evidence that this is crucial to concordance. If they are in doubt or dissatsfed they may turn to alternatve optons, including ‘complementary medicine’. There is no doubt that the medicine ‘doctor’ has a powerful efect to encourage confdence and perhaps contribute directly to the healing process. Prescripton Reasons Many aspects of the prescripton may lead to non-adherence (noncompliance). It may be illegible or inaccurate; it may get lost; it may not be reflled as intended or instructed for a chronic disease. Also, the prescripton may be too complex; it has been shown that the greater the number of medica- tons the poorer the adherence, while multple doses also decrease adherence if more than two doses per day are given. Not surprisingly adverse efects like drowsiness, impotence or nausea reduce adherence and patents may not admit to the problem. Pharmacist Reasons The pharmacist’s behaviour and professionalism, like the doctor’s, may have a positve impact, supportng adherence, or a negatve one, raising suspicions or concerns. This has been reported in relaton to generic drugs when substtuted for brand-name drugs. Pharmacist informaton and advice can be a valuable reinforcement, as long as it agrees with the doctor’s advice. The Healthcare System The healthcare system may be the biggest hindrance to adherence. Long waitng tmes, uncaring staf, uncomfortable environment, exhausted medicine supplies and so on, are all common problems in developing countries, and have a major impact on adherence. An important problem is the distance and accessibility of the clinic from the patent. Some studies have confrmed the obvious, that patents farthest from the clinic are least likely to adhere to treatment in the long term. They difer from accidental to deliberate excessive dosage or medicine maladministraton. Thalidomide marked the frst recognized public health disaster related to the introducton of a new medicine. It is now recognized that clinical trials, however thorough, cannot be guaranteed to detect all adverse efects likely to be caused by a medicine and hence necessitatng post-marketng surveillance. Health workers are thus encour- aged to record and report to the Natonal Pharmacovigilance Centre for any unexpected adverse efects with any medicine to achieve faster recogniton of serious related problems. Major Factors Predisposing to Adverse Efects It is well known that diferent patents ofen respond difer- ently to a given treatment regimen. For example, in a sample of 2422 patents who had been taking combinatons of drugs known to interact, only 7 (0. Drugs which commonly cause problems in the elderly include hypnotcs, diuretcs, non-steroidal ant-infamma- tory drugs, anthypertensives, psychotropics, digoxin etc. All children, and partcularly neonates, difer from adult in their response to drugs. Some drugs are likely to cause problems in neonates (for example morphine ), but are generally toler- ated in children. Other drugs associated with problems in children include chloramphenicol (grey baby syndrome), antarrhythmics (worsening of arrhythmias), acetylsalicylic acid (Reye’s syndrome etc). Drug Interactons Interactons (see Appendix 6) may occur between drugs which compete for the same receptor or act on the same physiolog- ical system. They may also occur indirectly when a medicine- induced disease or a change in fuid or electrolyte balance alters the response to another medicine. Interactons may occur when one medicine alters the absorpton, distributon, metabolism or eliminaton of another medicine, such that the amount which reaches the site of acton is increased or decreased. When two drugs are administered to a patent, they may either act independent of each other, or interact with each other. Interactons may increase or decrease the efects of the drugs concerned and may cause unexpected toxicity. As newer and more potent drugs become available, the number of serious medicine inter- actons is likely to increase.

Warnings/precautions • Use with caution in patients with heart failure order avana with paypal, kidney or liver disease avana 200mg sale. Advice to patient • Take missed drug as soon as remembered if within 4 hours of previous drug purchase avana. Clinically important drug interactions: Drugs that increase effects/ toxicity of tocainide: lidocaine cheap 50 mg avana free shipping, metoprolol, rifampin. Editorial comments • Tocainide is not often used because its side effects overshadow its efficacy as an antiarrhythmic. If the patient develops any signs of infection or excessive bruising or bleeding, complete blood counts should be performed promptly. If a hematologic disorder has been identified as being responsible, tocainide should be discontinued. Mechanism of action: Stimulates release of insulin from pancre- atic beta cells; decreases glucose production in liver; increases sensitivity of receptors for insulin, thereby enhancing effective- ness of insulin. Dose is best administered before breakfast or, if taken twice a day, before the evening meal. Contraindications: Hypersensitivity to the drug, diabetes com- plicated by ketoacidosis. Editorial comments • This drug is listed without details in the Physician’s Desk Reference, 54th edition, 2000. Mechanism of action: Stimulates release of insulin from pancre- atic beta cells; decreases glucose production in liver; increases sensitivity of receptors for insulin, thereby enhancing effec- tiveness of insulin. Dose is best administered before breakfast or, if taken twice a day, before the evening meal. Contraindications: Hypersensitivity to the drug, diabetes com- plicated by ketoacidosis. Editorial comments • This drug is listed without details in the Physician’s Desk Reference, 54th edition, 2000. Mechanism of action: Inhibits cyclooxygenase, resulting in inhi- bition of synthesis of prostaglandins and other inflammatory mediators. Indications/dosage/route • Rheumatoid arthritis, osteoarthritis Ð Adults: 400 mg t. Mechanism of action: Inhibits sodium and chloride reabsorp- tion in proximal part of ascending loop of Henle. Contraindications: Hypersensitivity to sulfonamides, anuria, hepa- tic coma, severe electrolyte depletion. Editorial comments • Torsemide has the advantage of a safer pregnancy category than other loop diuretics. Mechanism of action: Most likely produces analgesia by binding to opioid receptors. Adjustment of dosage • Kidney disease: Creatinine clearance <30 mL/min: 50–100 mg q12h. Contraindications: Hypersensitivity to tramadol or opioids; acute intoxication with alcohol; other analgesics, opioids, hypnotics, or psychotropic agents. There is an increased risk in patients with conditions that predispose to seizures, eg, head injury. Advice to patient • Avoid driving and other activities requiring mental alertness or that are potentially dangerous until response to drug is known. Sit at the edge of the bed for several minutes before standing, and lie down if feeling faint or dizzy. Adverse reactions • Common: dizziness, vertigo, headache, nausea, constipation, somnolence. In some clinical trials, tramadol was comparable or superior to adult dosages of codeine with/without acetaminophen. Use caution if administering to individuals with a prior history of opioid dependence or abuse of other drugs. Chronic dosage should be at lowest effective dose; downward titration is suggested. American Aca- demy of Pediatrics expresses concern regarding use of trazadone while breastfeeding. Warnings/precautions: Use with caution in patients with car- diac disease, risk of suicide. Adverse reactions • Common: dry mouth, dizziness, drowsiness, fatigue, insomnia, anxiety, nausea. Clinically important drug interactions: Trazodone increases effects/ toxicity of digoxin, phenytoin. Mechanism of action: Acts on distal renal tubules to inhibit sodium– potassium exchange. Adjustment of dosage • Kidney disease: Contraindicated in patients with anuria, acute and chronic renal insufficiency, or significant renal dysfunction. Contraindications: Anuria, hyperkalemia, severe renal insuffi- ciency, serum potassium level >5 mEq/L, patients receiving other potassium-sparing diuretics or potassium supplements, hypersensitivity to triamterine, significant renal dysfunction. Editorial comments • Use with caution in diabetics with those preparations combined with a thiazide diuretic, as they may worsen hyperglycemia. Use with caution in patients with history of kidney stones (triamterene may incorporate into stones). Mechanism of action: Blocks acetylcholine effects at muscarinic receptors throughout the body. Indications/dosage/route: Oral only • Parkinsonism Ð Adults: Initial, 1 mg on day 1. Contraindications: Injectable form in children, suppositories in premature and newborn infants, hypersensitivity to trimethoben- zamide, sensitivity to benzocaine (suppository). Warnings/precautions: Use with caution in uncomplicated vom- iting in children and in patients with febrile illness, encephalitides, gastroenteritis, dehydration, electrolyte imbalance. Advice to patient • Notify physician if worsening nausea develops, particularly if associated with fever, abdominal pain and/or distention, dizzi- ness, or headache. Adverse reactions • Common: drowsiness, hypotension, dizziness, headache, diar- rhea, muscle cramps. Clinically important drug interactions • Trimethobenzamide decreases effects/toxicity of oral anticoagulants. Editorial comments: The antiemetic action of trimethobenz- amide may obscure and render difficult the diagnosis of such conditions as appendicitis and evidence of toxicity due to over- dose of other drugs. Mechanism of action: Blocks folic acid synthesis, thus inhibit- ing biosynthesis of nucleic acids and proteins in susceptible organisms. Susceptible organisms in vivo • Gram positive: Streptococcus pneumoniae, Staphylococcus aureus, streptococci, Listeria. Adjustment of dosage • Kidney disease: Creatinine clearance >30 mL/min: usual dose; creatinine clearance 15–30 mL/min: 50% of usual dose; crea- tinine clearance <15 mL/min: not recommended. Food: Oral medication should be taken with 8 oz of water 1 hour before or 2 hours after eating. Contraindications: Hypersensitivity to trimethoprim or sulfona- mides, thiazide diuretics, oral hypoglycemics, megaloblastic anemia due to folate deficiency, pregnancy, lactation, treatment of streptococcal pharyngitis. Susceptible organisms in vivo: Staphylococcus pyogenes, Staphy- lococcus pneumoniae. Mechanism of action: Blocks nicotinic acetylcholine receptors at neuromuscular junction, resulting in skeletal muscle relax- ation and paralysis. Contraindications: Hypersensitivity to tubocurarine and chemi- cally related drugs. Warnings/precautions • Use with caution in patients with liver disease, kidney disease, impaired pulmonary function, respiratory depression, myasthenia gravis, dehydration, porphyria, muscle spasms, hypokalemia, hypermagnesemia, dehydration, underlying cardiovascular dis- ease, fractures, hyperthermia, shock, thyroid disorders, famil- ial periodic paralysis. Accordingly, an antianxiety agent (benzodiazepine) or analgesic (narcotic) is administered along with these drugs. Accordingly, appro- priate measures must be on hand to provide respiratory support should this be necessary. As consciousness is not affected by the drug, use caution in conversation near patient. Clinically important drug interactions: Drugs that increase effects/ toxicity of neuromuscular blockers: inhalation anesthetics, amino- glycosides, quinidine, lincomycin, tetracycline, lithium, magne- sium sulfate, polymyxin D, vancomycin, bacitracin, colistin. If respiratory depression persists, administer a cholinesterase inhibitor, eg, neostigmine or pyridostigmine. Editorial comments • Neuromuscular blocking drugs should be administered by or under supervision of experienced clinicians who are thor- oughly familiar with these drugs and know how to treat potential complications that might arise from their use.