Techno assignment 3 marks
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Nifedipine is the active ingredient in PROCARDIA XL, which is an extended release tablet used to treat hypertension and chest pain called angina. It works by blocking calcium channels and relaxing blood vessels. PROCARDIA XL tablets have an osmotic pump system that slowly releases nifedipine over 24 hours for continuous effect. Common side effects include headache, dizziness, and ankle swelling. It can be used alone or combined with other blood pressure medications and is generally started at a low dose that is increased gradually based on the patient's response.
Techno assignment 3 marks
- 1. Pharmaceutical Technology PROCARDIA XL Nifedipine is a drug belonging to a class of pharmacological agents known as the calcium channel blockers. Nifedipine is 3,5- pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-4(2- nitrophenyl)-, dimethyl ester, C17H18N2O6, and has the structural formula: Nifedipine is a yellow crystalline substance, practically insoluble in water but soluble in ethanol. It has a molecular weight of 346.3. PROCARDIA XL is a registered trademark for Nifedipine GITS. Nifedipine GITS (Gastrointestinal Therapeutic System) Tablet is formulated as a once-a-day controlled- release tablet for oral administration designed to deliver 30, 60, or 90 mg of nifedipine. Inert ingredients in the formulations are: cellulose acetate; hydroxypropyl cellulose; hypromellose; magnesium stearate; polyethylene glycol; polyethylene oxide; red ferric oxide; sodium chloride; titanium dioxide. PROCARDIA XL® Extended Release Tablet is similar in appearance to a conventional tablet. It consists, however, of a semipermeable membrane surrounding an osmotically active drug core. The core itself is divided into two layers: an “active” layer containing the drug, and a “push” layer containing pharmacologically inert (but osmotically active) components. As water from the gastrointestinal tract enters the tablet, pressure increases in the osmotic layer and “pushes” against the drug layer, releasing drug through the precision laser-drilled tablet orifice in the active layer. PROCARDIA XL Extended Release Tablet is designed to provide nifedipine at an approximately constant rate over 24 hours. This controlled rate of drug delivery into the gastrointestinal lumen is independent of pH or gastrointestinal motility. PROCARDIA XL depends for its action on the existence of an osmotic gradient between the contents of the bi-layer core and fluid in the gastrointestinal tract. Drug delivery is essentially constant as long as the osmotic gradient remains constant, and then gradually falls to zero. Upon swallowing, the biologically inert components of the tablet remain intact during gastrointestinal transit and are eliminated in the feces as an insoluble shell. Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you have a serious side effect such as: worsening angina; severe constipation and cramps, severe stomach pain or heartburn, coughing up blood; feeling like you might pass out; feeling short of breath, swelling in your hands or feet; fast or pounding heartbeats; numbness or tingly feeling; Jaundice (yellowing of the skin or eyes);
- 2. Techno Assignment by Group 06 Page 1 Before taking this medication, tell your doctor or pharmacist if you are allergic to it; or to other calcium channel blockers (e.g., amlodipine, felodipine); or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details. Before using this medication, tell your doctor or pharmacist your medical history, especially of: heart diseases (e.g., congestive heart failure, aortic stenosis), liver problems, esophagus/stomach/intestine problems (e.g., narrowing/stricture, motility disorders, obstruction), kidney problems, a certain metabolic disorder (porphyria). INDICATIONS Vasospastic Angina PROCARDIA XL is indicated for the management of vasospastic angina confirmed by any of the following criteria: 1) classical pattern of angina at rest accompanied by ST segment elevation, 2) angina or coronary artery spasm provoked by ergonovine, or 3) angiographically demonstrated coronary artery spasm. In those patients who have had angiography, the presence of significant fixed obstructive disease is not incompatible with the diagnosis of vasospastic angina, provided that the above criteria are satisfied. PROCARDIA XL may also be used where the clinical presentation suggests a possible vasospastic component, but where vasospasm has not been confirmed, e.g., where pain has a variable threshold on exertion, or in unstable angina where electrocardiographic findings are compatible with intermittent vasospasm, or when angina is refractory to nitrates and/or adequate doses of beta blockers. Chronic Stable Angina (Classical Effort-Associated Angina) PROCARDIA XL is indicated for the management of chronic stable angina (effort-associated angina) without evidence of vasospasm in patients who remain symptomatic despite adequate doses of beta blockers and/or organic nitrates or who cannot tolerate those agents. In chronic stable angina (effort-associated angina), nifedipine has been effective in controlled trials of up to eight weeks duration in reducing angina frequency and increasing exercise tolerance, but confirmation of sustained effectiveness and evaluation of long-term safety in these patients is incomplete. Controlled studies in small numbers of patients suggest concomitant use of nifedipine and beta-blocking agents may be beneficial in patients with chronic stable angina, but available information is not sufficient to predict with confidence the effects of concurrent treatment, especially in patients with compromised left ventricular function or cardiac conduction abnormalities. When introducing such concomitant therapy, care must be taken to monitor blood pressure closely, since severe hypotension can occur from the combined effects of the drugs. Hypertension PROCARDIA XL is 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 PROCARDIA XL. 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
- 3. Techno Assignment by Group 06 Page 2 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 classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy. PROCARDIA XL may be used alone or in combination with other antihypertensive agents. DOSAGE AND ADMINISTRATION Dosage must be adjusted according to each patient's needs. Therapy for either hypertension or angina should be initiated with 30 or 60 mg once daily. PROCARDIA XL Extended Release Tablets should be swallowed whole and should not be bitten or divided. In general, titration should proceed over a 7–14 day period so that the physician can fully assess the response to each dose level and monitor blood pressure before proceeding to higher doses. Since steady-state plasma levels are achieved on the second day of dosing, titration may proceed more rapidly, if symptoms so warrant, provided the patient is assessed frequently. Titrations to doses above 120 mg are not recommended. Angina patients controlled on PROCARDIA capsules alone or in combination with other antianginal medications may be safely switched to PROCARDIA XL Extended Release Tablets at the nearest equivalent total daily dose (e.g., 30 mg t.i.d. of PROCARDIA capsules may be changed to 90 mg once daily of PROCARDIA XL Extended Release Tablets). Subsequent titration to higher or lower doses may be necessary and should be initiated as clinically warranted. Experience with doses greater than 90 mg in patients with angina is limited. Therefore, doses greater than 90 mg should be used with caution and only when clinically warranted. Avoid co-administration of nifedipine with grapefruit juice. No “rebound effect” has been observed upon discontinuation of PROCARDIA XL Extended Release Tablets. However, if discontinuation of nifedipine is necessary, sound clinical practice suggests that the dosage should be decreased gradually with close physician supervision. Care should be taken when dispensing PROCARDIA XL to assure that the extended release dosage form has been prescribed. Co-Administration With Other Antianginal Drugs Sublingual nitroglycerin may be taken as required for the control of acute manifestations of angina, particularly during nifedipine titration.
- 4. Techno Assignment by Group 06 Page 3 DRUG INTERACTIONS Beta-adrenergic blocking agents Experience in over 1400 patients with PROCARDIA capsules in a noncomparative clinical trial has shown that concomitant administration of nifedipine and beta-blocking agents is usually well tolerated, but there have been occasional literature reports suggesting that the combination may increase the likelihood of congestive heart failure, severe hypotension, or exacerbation of angina. Long-acting Nitrates Nifedipine may be safely co-administered with nitrates, but there have been no controlled studies to evaluate the antianginal effectiveness of this combination. Digitalis Administration of nifedipine with digoxin increased digoxin levels in nine of twelve normal volunteers. The average increase was 45%. Another investigator found no increase in digoxin levels in thirteen patients with coronary artery disease. In an uncontrolled study of over two hundred patients with congestive heart failure during which digoxin blood levels were not measured, digitalis toxicity was not observed. Since there have been isolated reports of patients with elevated digoxin levels, it is recommended that digoxin levels be monitored when initiating, adjusting, and discontinuing nifedipine to avoid possible over-or under-digitalization. Coumarin Anticoagulants There have been rare reports of increased prothrombin time in patients taking coumarin anticoagulants to whom nifedipine was administered. However, the relationship to nifedipine therapy is uncertain. Cimetidine A study in six healthy volunteers has shown a significant increase in peak nifedipine plasma levels (80%) and area-under-the-curve (74%), after a one week course of cimetidine at 1000 mg per day and nifedipine at 40 mg per day. Ranitidine produced smaller, non-significant increases. The effect may be mediated by the known inhibition of cimetidine on hepatic cytochrome P-450, the enzyme system probably responsible for the first-pass metabolism of nifedipine. If nifedipine therapy is initiated in a patient currently receiving cimetidine, cautious titration is advised. Nifedipine is metabolized by CYP3A4. Co-administration of nifedipine with phenytoin, an inducer of CYP3A4, lowers the systemic exposure to nifedipine by approximately 70%. Avoid co-administration of nifedipine with phenytoin or any known CYP3A4 inducer or consider an alternative antihypertensive therapy. Other Interactions (Grapefruit Juice) Co-administration of nifedipine with grapefruit juice resulted in approximately a doubling in nifedipine AUC and Cmax with no change in half-life. The increased plasma concentrations most likely result from inhibition of CYP 3A4 related first-pass metabolism. Avoid ingestion of grapefruit and grapefruit juice should be avoided while taking nifedipine.
- 5. Techno Assignment by Group 06 Page 4 CLINICAL PHARMACOLOGY Nifedipine is a calcium ion influx inhibitor (slow-channel blocker or calcium ion antagonist) and inhibits the transmembrane influx of calcium ions into cardiac muscle and smooth muscle. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Nifedipine selectively inhibits calcium ion influx across the cell membrane of cardiac muscle and vascular smooth muscle without altering serum calcium concentrations. Mechanism of Action Angina The precise mechanisms by which inhibition of calcium influx relieves angina has not been fully determined, but includes at least the following two mechanisms: Relaxation and Prevention of Coronary Artery Spasm Nifedipine dilates the main coronary arteries and coronary arterioles, both in normal and ischemic regions, and is a potent inhibitor of coronary artery spasm, whether spontaneous or ergonovine-induced. This property increases myocardial oxygen delivery in patients with coronary artery spasm, and is responsible for the effectiveness of nifedipine in vasospastic (Prinzmetal's or variant) angina. Whether this effect plays any role in classical angina is not clear, but studies of exercise tolerance have not shown an increase in the maximum exercise rate-pressure product, a widely accepted measure of oxygen utilization. This suggests that, in general, relief of spasm or dilation of coronary arteries is not an important factor in classical angina. Reduction of Oxygen Utilization Nifedipine regularly reduces arterial pressure at rest and at a given level of exercise by dilating peripheral arterioles and reducing the total peripheral vascular resistance (afterload) against which the heart works. This unloading of the heart reduces myocardial energy consumption and oxygen requirements, and probably accounts for the effectiveness of nifedipine in chronic stable angina. Hypertension The mechanism by which nifedipine reduces arterial blood pressure involves peripheral arterial vasodilatation and the resulting reduction in peripheral vascular resistance. The increased peripheral vascular resistance that is an underlying cause of hypertension results from an increase in active tension in the vascular smooth muscle. Studies have demonstrated that the increase in active tension reflects an increase in cytosolic free calcium. Nifedipine is a peripheral arterial vasodilator which acts directly on vascular smooth muscle. The binding of nifedipine to voltage-dependent and possibly receptor-operated channels in vascular smooth muscle results in an inhibition of calcium influx through these channels. Stores of intracellular calcium in vascular smooth muscle are limited and thus dependent upon the influx of extracellular calcium for contraction to occur. The reduction in calcium influx by nifedipine causes arterial vasodilation and decreased peripheral vascular resistance which results in reduced arterial blood pressure. Pharmacokinetics And Metabolism
- 6. Techno Assignment by Group 06 Page 5 Nifedipine is completely absorbed after oral administration. Plasma drug concentrations rise at a gradual, controlled rate after a PROCARDIA XL Extended Release Tablet dose and reach a plateau at approximately six hours after the first dose. For subsequent doses, relatively constant plasma concentrations at this plateau are maintained with minimal fluctuations over the 24-hour dosing interval. About a four-fold higher fluctuation index (ratio of peak to trough plasma concentration) was observed with the conventional immediate-release PROCARDIA® capsule at t.i.d. dosing than with once daily PROCARDIA XL Extended Release Tablet. At steady-state, the bioavailability of the PROCARDIA XL Extended Release Tablet is 86% relative to PROCARDIA capsules. Administration of the PROCARDIA XL Extended Release Tablet in the presence of food slightly alters the early rate of drug absorption, but does not influence the extent of drug bioavailability. Markedly reduced gastrointestinal retention time over prolonged periods (i.e., short bowel syndrome), however, may influence the pharmacokinetic profile of the drug which could potentially result in lower plasma concentrations. Pharmacokinetics of PROCARDIA XL Extended Release Tablets are linear over the dose range of 30 to 180 mg in that plasma drug concentrations are proportional to dose administered. There was no evidence of dose dumping either in the presence or absence of food for over 150 subjects in pharmacokinetic studies. Nifedipine is extensively metabolized to highly water-soluble, inactive metabolites, accounting for 60 to 80% of the dose excreted in the urine. The elimination half-life of nifedipine is approximately two hours. Only traces (less than 0.1% of the dose) of unchanged form can be detected in the urine. The remainder is excreted in the feces in metabolized form, most likely as a result of biliary excretion. Thus, the pharmacokinetics of nifedipine are not significantly influenced by the degree of renal impairment. Patients in hemodialysis or chronic ambulatory peritoneal dialysis have not reported significantly altered pharmacokinetics of nifedipine. Since hepatic biotransformation is the predominant route for the disposition of nifedipine, the pharmacokinetics may be altered in patients with chronic liver disease. Patients with hepatic impairment (liver cirrhosis) have a longer disposition half-life and higher bioavailability of nifedipine than healthy volunteers. The degree of serum protein binding of nifedipine is high (92–98%). Protein binding may be greatly reduced in patients with renal or hepatic impairment. Following intravenous administration, clearance of nifedipine was decreased by 33% in elderly healthy subjects relative to young healthy subjects. Hemodynamics Like other slow-channel blockers, nifedipine exerts a negative inotropic effect on isolated myocardial tissue. This is rarely, if ever, seen in intact animals or man, probably because of reflex responses to its vasodilating effects. In man, nifedipine decreases peripheral vascular resistance which leads to a fall in systolic and diastolic pressures, usually minimal in normotensive volunteers (less than 5–10 mm Hg systolic), but sometimes larger. With PROCARDIA XL Extended Release Tablets, these decreases in blood pressure are not accompanied by any significant change in heart rate. Hemodynamic studies in patients with normal ventricular function have generally found a small increase in cardiac index without major effects on ejection fraction, left ventricular end diastolic pressure (LVEDP), or volume (LVEDV). In patients with impaired ventricular function, most acute studies have shown some increase in ejection fraction and reduction in left ventricular filling pressure. Electrophysiologic Effects Although, like other members of its class, nifedipine causes a slight depression of sinoatrial node function and atrioventricular conduction in isolated myocardial preparations, such effects have not been seen in studies in intact animals or in man. In formal electrophysiologic studies, predominantly in patients with
- 7. Techno Assignment by Group 06 Page 6 normal conduction systems, nifedipine has had no tendency to prolong atrioventricular conduction or sinus node recovery time, or to slow sinus rate.
- 8. Techno Assignment by Group 06 Page 7 LUPRON DEPOT Leuprolide acetate is a synthetic nonapeptide analog of naturally occurring gonadotropin-releasing hormone (GnRH). The analog possesses greater potency than the natural hormone. The chemical name is 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucylL-arginyl-N-ethyl-L- prolinamide acetate (salt) with the following structural formula: LUPRON DEPOT 7.5 mg for 1-month administration is available in a prefilled dual-chamber syringe containing sterile lyophilized microspheres which, when mixed with diluent, becomes a suspension intended as a monthly intramuscular injection. The front chamber of LUPRON DEPOT 7.5 mg for 1-month administration prefilled dual-chamber syringe contains leuprolide acetate (7.5 mg), purified gelatin (1.3 mg), DL-lactic and glycolic acids copolymer (66.2 mg), and D-mannitol (13.2 mg). The second chamber of diluent contains carboxymethylcellulose sodium (5 mg), D-mannitol (50 mg), polysorbate 80 (1 mg), water for injection, USP, and glacial acetic acid, USP to control pH. LUPRON DEPOT 22.5 mg for 3-month administration is available in a prefilled dual-chamber syringe containing sterile lyophilized microspheres which, when mixed with diluent, become a suspension intended as an intramuscular injection to be given ONCE EVERY 12 WEEKS. The front chamber of LUPRON DEPOT 22.5 mg for 3-month administration prefilled dual-chamber syringe contains leuprolide acetate (22.5 mg), polylactic acid (198.6 mg) and Dmannitol (38.9 mg). The second chamber of diluent contains carboxymethylcellulose sodium (7.5 mg), D-mannitol (75.0 mg), polysorbate 80 (1.5 mg), water for injection, USP, and glacial acetic acid, USP to control pH. LUPRON DEPOT 30 mg for 4-month administration is available in a prefilled dual-chamber syringe containing sterile lyophilized microspheres which, when mixed with diluent, become a suspension intended as an intramuscular injection to be given ONCE EVERY 16 WEEKS. The front chamber of LUPRON DEPOT 30 mg for 4-month administration prefilled dual-chamber syringe contains leuprolide acetate (30 mg), polylactic acid (264.8 mg) and D-mannitol (51.9 mg). The second chamber of diluent contains carboxymethylcellulose sodium (7.5 mg), Dmannitol (75.0 mg), polysorbate 80 (1.5 mg), water for injection, USP, and glacial acetic acid, USP to control pH. LUPRON DEPOT 45 mg for 6-month administration is available in a prefilled dual-chamber syringe containing sterile lyophilized microspheres which, when mixed with diluent, become a suspension intended as an intramuscular injection to be given ONCE EVERY 24 WEEKS. The front chamber of LUPRON DEPOT 45 mg for 6-month administration prefilled dual-chamber syringe contains leuprolide acetate (45 mg), polylactic acid (169.9 mg), D-mannitol (39.7 mg), and stearic acid (10.1 mg). The second chamber of diluent contains carboxymethylcellulose sodium (7.5 mg), D-mannitol
- 9. Techno Assignment by Group 06 Page 8 (75.0 mg), polysorbate 80 (1.5 mg), water for injection, USP, and glacial acetic acid, USP to control pH.Use LUPRON DEPOT® (leuprolide acetate for depot suspension) 3.75 mg for 1-month and 11.25 mg for 3- month administration are used for the management of endometriosis, including pain relief and reduction of endometriotic lesions. LUPRON DEPOT with daily norethindrone acetate 5 mg is also indicated for initial management of endometriosis and for management of recurrence of symptoms. The recommended initial treatment is no more than 6 months. Repeat treatment for endometriosis should be limited to 6 months. Important Safety Information Do not take LUPRON DEPOT if you are or may become pregnant, are breast-feeding, have undiagnosed vaginal bleeding, or if you have experienced any type of allergic reaction to LUPRON DEPOT, or similar drugs. You should not take norethindrone acetate with LUPRON DEPOT if you currently have or have previously had any clotting disorder, heart disease, stroke, impaired liver function or liver disease, or breast cancer. Tell your health care provider before beginning treatment with norethindrone acetate if you currently have or have previously had high cholesterol, migraines, epilepsy, depression, or smoke. During treatment with LUPRON DEPOT and norethindrone acetate, immediately tell your doctor if you have a sudden loss of vision, double vision, or if migraine headaches occur. You should notify your doctor if you experience fluid retention, seizure, asthma or worsening of asthmatic symptoms, heart or kidney problems. Thinning of the bones may occur during therapy with LUPRON DEPOT alone, which may not be completely reversible in some patients. Since some conditions may increase the possibility of bone thinning, you should tell your doctor if you smoke, use alcohol in excess, have a family history of osteoporosis (thinning of the bones with fractures), or are taking other medications that can cause thinning of the bones. You should be aware that if you have these conditions, treatment with LUPRON DEPOT alone is not advisable and combination with norethindrone acetate should be considered. If a second course of treatment with LUPRON DEPOT is being considered, bone mineral testing is recommended and retreatment should include combination with norethindrone acetate. After beginning LUPRON DEPOT, your estrogen levels will increase for 1 or 2 weeks. During this time, you may notice an increase in your current symptoms. You should notify your doctor if you develop any new or worsened symptoms after beginning LUPRON DEPOT treatment. LUPRON DEPOT is not a method of birth control. Even though you may not have periods, unprotected intercourse could result in pregnancy. You should use non-hormonal birth control, such as condoms, a diaphragm with contraceptive jelly, or a copper IUD, to prevent pregnancy. If you think you have become pregnant while on LUPRON DEPOT, talk to your doctor immediately. There is a possibility of the development or worsening of depression and/or the occurrence of forgetfulness. Patients who have a history of depression should be carefully observed during treatment. Convulsions have been observed in patients taking leuprolide acetate. The most common side effects of LUPRON DEPOT include hot flashes, vaginal dryness, headaches, changes in mood, decreased interest in sex, depression, and/or the occurrence of forgetfulness. LUPRON DEPOT must be administered in your doctor’s office.
- 10. Techno Assignment by Group 06 Page 9 CLINICAL PHARMACOLOGY Mechanism Of Action: Leuprolide acetate, a GnRH agonist, acts as an inhibitor of gonadotropin secretion. Animal studies indicate that following an initial stimulation, continuous administration of leuprolide acetate results in suppression of ovarian and testicular steroidogenesis. This effect was reversible upon discontinuation of drug therapy. Administration of leuprolide acetate has resulted in inhibition of the growth of certain hormone dependent tumors (prostatic tumors in Noble and Dunning male rats and DMBA-induced mammary tumors in female rats) as well as atrophy of the reproductive organs. Pharmacodynamics: In humans, administration of leuprolide acetate results in an initial increase in circulating concentrations of luteinizing hormone (LH) and follicle stimulating hormone (FSH), leading to a transient increase in concentrations of the gonadal steroids (testosterone and dihydrotestosterone in males, and estrone and estradiol in premenopausal females). However, continuous administration of leuprolide acetate results in decreased concentrations of LH and FSH. In males, testosterone is reduced to castrate concentrations. In premenopausal females, estrogens are reduced to postmenopausal concentrations. These decreases occur within two to four weeks after initiation of treatment, and castrate concentrations of testosterone in prostatic cancer patients have been demonstrated for more than five years. Leuprolide acetate is not active when given orally. Pharmacokinetics: Absorption LUPRON DEPOT 7.5 mg For 1-Month Administration: Following a single injection of LUPRON DEPOT 7.5 mg for 1-month administration to patients, mean plasma measured concentrations were 20 ng/mL at 4 hours and 0.36 ng/mL at 4 weeks. However, intact leuprolide and an inactive major metabolite could not be distinguished by the assay which was employed in the study. LUPRON DEPOT 22.5 mg For 3-Month Administration: Following a single injection of LUPRON DEPOT 22.5 mg for 3-month administration in patients, mean peak plasma concentrations were 48.9 ng/mL at 4 hours and then declined to 0.67 ng/mL at 12 weeks. Leuprolide appeared to be released at a constant rate following the onset of steady-state concentrations during the third week after dosing, providing steady plasma concentrations through the 12-week dosing interval. However, intact leuprolide and an inactive major metabolite could not be distinguished by the assay which was employed in the study. The initial burst, followed by a decline to a steady-state concentration, was similar to the release pattern seen with the monthly formulation. LUPRON DEPOT 45 mg For 6-Month Administration: Following a single injection of LUPRON DEPOT 45 mg for 6-month administration in 26 prostate cancer patients, mean peak plasma concentration of 6.7 ng/mL was observed at 2 hours and then declined to 0.07 ng/mL at 24 weeks. Leuprolide appeared to be released continuously following the onset of steady-state concentrations during the third week after dosing providing steady plasma concentrations through the 24-week dosing interval. The initial burst, followed by a decline to a steady-state concentration, was similar to the release pattern seen with the other depot formulations. In this study, mean plasma concentration-time profiles were similar after the first and second dose. Distribution: The mean steady-state volume of distribution of leuprolide following intravenous bolus administration to healthy male volunteers was 27 L. In vitro binding to human plasma proteins ranged from 43% to 49%. Elimination: The mean systemic clearance of leuprolide following intravenous bolus administration to healthy male volunteers was 7.6 L/h, and terminal elimination half-life was approximately 3 hours based on a two compartment model.
- 11. Techno Assignment by Group 06 Page 10 NORPLANT The NORPLANT SYSTEM kit contains levonorgestrel implants, a set of six flexible closed capsules made of silicone rubber tubing (Silastic® , dimethylsiloxane/methylvinylsiloxane copolymer), each containing 36 mg of the progestin levonorgestrel contained in an insertion kit to facilitate implantation. The capsules are sealed with Silastic (polydimethylsiloxane) adhesive and sterilized. Each capsule is 2.4 mm in diameter and 34 mm in length. The capsules are inserted in a superficial plane beneath the skin of the upper arm. Information contained herewith regarding safety and efficacy was derived from studies which used two slightly different Silastic tubing formulations. The formulation being used in the NORPLANT SYSTEM has slightly higher release rates of levonorgestrel and at least comparable efficacy. Evidence indicates that the dose of levonorgestrel provided by the NORPLANT (levonorgestrel implants unavailable in us) SYSTEM is initially about 85 mcg/day followed by a decline to about 50 mcg/day by 9 months and to about 35 mcg/day by 18 months with a further decline thereafter to about 30 mcg/day. The NORPLANT (levonorgestrel implants unavailable in us) SYSTEM is a progestin-only product and does not contain estrogen. Levonorgestrel, (18,19-Dinorpregn-4-en-20-yn- 3-one, 13-ethyl-17-hydroxy-, (17α)-(–)-), the active ingredient in the NORPLANT (levonorgestrel implants unavailable in us) SYSTEM, has a molecular weight of 312.45 and the following structural formula: Levonorgestrel (C21H28O2) The NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM is indicated for the prevention of pregnancy and is a long-term (up to 5 years) reversible contraceptive system. The capsules should be removed by the end of the 5th year. New capsules may be inserted at that time if continuing contraceptive protection is desired. DOSAGE AND ADMINISTRATION: The NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM consists of six Silastic® capsules, each containing 36 mg of the progestin, levonorgestrel. The total administered (implanted) dose is 216 mg. Implantation of all six capsules should be performed during the first 7 days of the onset of menses by a health-care professional instructed in the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM insertion technique. Insertion is subdermal in the midportion of the upper arm about 8 to 10 cm above the elbow crease. Distribution should be in a fanlike pattern, about 15 degrees apart, for a total of 75 degrees. Proper insertion will facilitate later removal. SIDE EFFECTS: The following adverse reactions have been associated with the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM during the first year of use in clinical trials: Many bleeding days or prolonged bleeding 27.6% Spotting 17.1% Amenorrhea 9.4% Irregular (onsets of) bleeding 7.6% Frequent bleeding onsets 7.0% Scanty bleeding 5.2% Painor itchingnearimplantsite (usuallytransient) 3.7% Infection at implant site 0.7%
- 12. Techno Assignment by Group 06 Page 11 DRUG INTERACTIONS: Reduced efficacy (pregnancy) has been reported for NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM users taking phenytoin and carbamazepine. These drugs may increase the metabolism of levonorgestrel through induction of microsomal liver enzymes. NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM users should be warned of the possibility of decreased efficacy with the use of drugs exhibiting enzyme-inducing activity such as those noted above and rifampin. For women receiving long-term therapy with hepatic enzyme inducers, another method of contraception should be considered. Drug/Laboratory Test Interactions: Certain endocrine tests may be affected by NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM use: 1. Sex-hormone-binding globulin concentrations are decreased. 2. Thyroxine concentrations may be slightly decreased and triiodothyronine uptake increased. CLINICAL PHARMACOLOGY Levonorgestrel is a totally synthetic and biologically active progestin which exhibits no significant estrogenic activity and is highly progestational. The absolute configuration conforms to that of D-natural steroids. Levonorgestrel is not subjected to a “first-pass” effect and is virtually 100% bioavailable. Plasma concentrations average approximately 0.30 ng/mL over 5 years but are highly variable as a function of individual metabolism and body weight. Diffusion of levonorgestrel through the wall of each capsule provides a continuous low dose of the progestin. Resulting blood levels are substantially below those generally observed among users of combination oral contraceptives containing the progestins norgestrel or levonorgestrel. Because of the range of variability in blood levels and variation in individual response, blood levels alone are not predictive of the risk of pregnancy in an individual woman. At least two mechanisms are active in preventing pregnancy: ovulation inhibition and thickening of the cervical mucus. Other mechanisms may add to these contraceptive effects. Levonorgestrel concentrations among women show considerable variation depending on individual clearance rates, body weight, and possibly other factors. Levonorgestrel concentrations reach a maximum, or near maximum, within 24 hours after placement with mean values of 1600 ± 1100 pg/mL. They decline rapidly over the first month partially due to a circulating protein, SHBG, that binds levonorgestrel and which is depressed by the presence of levonorgestrel. At 3 months, mean levels decline to values of around 400 pg/mL while concentrations normalized to a 60 kg body weight were 327 ± 119 (SD) pg/mL at 12 months with further decline by 1.4 pg/mL/month to reach 258 ± 95 (SD) pg/mL at 60 months. Concentrations decreased with increasing body weight by a mean of 3.3 pg/mL/kg. After capsule removal, mean concentrations drop to below 100 pg/mL by 96 hours and to below assay sensitivity (50 pg/mL) by 5 to 14 days. Fertility rates return to levels comparable to those seen in the general population of women using no method of contraception. Circulating concentrations can be used to forecast the risk of pregnancy only in a general statistical sense. Mean concentrations associated with pregnancy have been 210 ± 60 (SD) pg/mL. However, in clinical studies, 20 percent of women had one or more values below 200 pg/mL but an average annual gross pregnancy rate of less than 1.0 per 100 women through 5 years. CONTRAINDICATIONS 1. Active thrombophlebitis or thromboembolic disorders. There is insufficient information regarding women who have had previous thromboembolic disease. 2. Undiagnosed abnormal genital bleeding. 3. Known or suspected pregnancy. 4. Acute liver disease; benign or malignant liver tumors. 5. Known or suspected carcinoma of the breast. 6. History of idiopathic intracranial hypertension. 7. Hypersensitivity to levonorgestrel or any of the other components of the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM.