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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.