Ambroxol Stada may be available in the countries listed below.
Ambroxol hydrochloride (a derivative of Ambroxol) is reported as an ingredient of Ambroxol Stada in the following countries:
International Drug Name Search
Propranolol hydrochloride and hydrochlorothiazide tablets, USP for oral administration combine two antihypertensive agents: propranolol hydrochloride, USP, a beta-adrenergic blocking agent, and hydrochlorothiazide, USP, a thiazide diuretic-antihypertensive. Propranolol hydrochloride and hydrochlorothiazide tablets, 40/25 contain 40 mg propranolol hydrochloride and 25 mg hydrochlorothiazide; propranolol hydrochloride and hydrochlorothiazide tablets, 80/25 contain 80 mg propranolol hydrochloride and 25 mg hydrochlorothiazide.
Propranolol hydrochloride is a synthetic beta-adrenergic receptor-blocking agent chemically described as 1-(Isopropylamino)-3-(1-naphthyloxy)-2-propanol hydrochloride. Its structural formula is:
Propranolol hydrochloride, USP is a stable, white, crystalline solid which is readily soluble in water and ethanol. Its molecular weight is 295.81.
Hydrochlorothiazide, USP is a white, or practically white, practically odorless, crystalline powder. It is slightly soluble in water; freely soluble in sodium hydroxide solution; sparingly soluble in methanol; insoluble in ether, chloroform, benzene, and dilute mineral acids. Its chemical name is: 6-Chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its structural formula is:
Propranolol hydrochloride and hydrochlorothiazide tablets, 40 mg/25 mg and 80 mg/25 mg are for oral administration and contain the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, pregelatinized cornstarch and sodium lauryl sulfate.
Propranolol hydrochloride is a nonselective beta-adrenergic receptor blocking agent possessing no other autonomic nervous system activity. It specifically competes with beta-adrenergic receptor stimulating agents for available receptor sites. When access to beta-receptor sites is blocked by propranolol, the chronotropic, inotropic, and vasodilator responses to beta-adrenergic stimulation are decreased proportionately.
Propranolol is almost completely absorbed from the gastrointestinal tract, but a portion is immediately metabolized by the liver on its first pass through the portal circulation.
Peak effect occurs in one to one-and-one-half hours. The biologic half-life is approximately 4 hours. Propranolol is not significantly dialyzable. There is no simple correlation between dose or plasma level and therapeutic effect, and the dose-sensitivity range, as observed in clinical practice, is wide. The principal reason for this is that sympathetic tone varies widely between individuals. Since there is no reliable test to estimate sympathetic tone or to determine whether total beta-blockade has been achieved, proper dosage requires titration.
The mechanism of the antihypertensive effect of propranolol has not been established. Among the factors that may be involved in contributing to the antihypertensive action are (1) decreased cardiac output, (2) inhibition of renin release by the kidneys, and (3) diminution of tonic sympathetic nerve outflow from vasomotor centers in the brain. Although total peripheral resistance may increase initially, it readjusts to, or below, the pretreatment level with chronic use. Effects on plasma volume appear to be minor and somewhat variable. Propranolol has been shown to cause a small increase in serum potassium concentration when used in the treatment of hypertensive patients. Propranolol hydrochloride decreases heart rate, cardiac output, and blood pressure.
Beta-receptor blockade can be useful in conditions in which, because of pathologic or functional changes, sympathetic activity is detrimental to the patient. But there are also situations in which sympathetic stimulation is vital. For example, in patients with severely damaged hearts, adequate ventricular function is maintained by virtue of sympathetic drive, which should be preserved. In the presence of AV block greater than first degree, beta-blockade may prevent the necessary facilitating effect of sympathetic activity on conduction. Beta-blockade results in bronchial constriction by interfering with adrenergic bronchodilator activity, which should be preserved in patients subject to bronchospasm.
The proper objective of beta-blockade therapy is to decrease adverse sympathetic stimulation, but not to the degree that may impair necessary sympathetic support.
Hydrochlorothiazide is a benzothiadiazine (thiazide) diuretic closely related to chlorothiazide. The mechanism of the antihypertensive effect of the thiazides is unknown. Thiazides do not affect normal blood pressure.
Thiazides affect the renal tubular mechanism of electrolyte reabsorption. At maximal therapeutic dosage, all thiazides are approximately equal in their diuretic potency.
Thiazides increase excretion of sodium and chloride in approximately equivalent amounts. Natriuresis causes a secondary loss of potassium and bicarbonate. Onset of diuretic action of hydrochlorothiazide occurs in 2 hours, and the peak effect in about 4 hours. Its action persists for approximately 6 to 12 hours. Thiazides are eliminated rapidly by the kidney.
Propranolol hydrochloride and hydrochlorothiazide tablets are indicated in the management of hypertension.
This fixed combination is not indicated for initial therapy of hypertension. Hypertension requires therapy titrated to the individual patient. If the fixed combination represents the dosage so determined, its use may be more convenient in patient management.
Propranolol is contraindicated in 1) cardiogenic shock; 2) sinus bradycardia and greater than first-degree block; 3) bronchial asthma; 4) congestive heart failure (see WARNINGS) unless the failure is secondary to a tachyarrhythmia treatable with propranolol.
Hydrochlorothiazide is contraindicated in patients with anuria or hypersensitivity to this or other sulfonamide-derived drugs.
Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, have been associated with the administration of Propranolol and Hydrochlorothiazide (see ADVERSE REACTIONS).
Sympathetic stimulation is a vital component supporting circulatory function in congestive heart failure, and inhibition with beta-blockade always carries the potential hazard of further depressing myocardial contractility and precipitating cardiac failure. Propranolol acts selectively without abolishing the inotropic action of digitalis on the heart muscle (i.e., that of supporting the strength of myocardial contractions). In patients already receiving digitalis, the positive inotropic action of digitalis may be reduced by propranolol’s negative inotropic effect.
Continued depression of the myocardium over a period of time can, in some cases, lead to cardiac failure. In rare instances, this has been observed during propranolol therapy. Therefore, at the first sign or symptom of impending cardiac failure, patients should be fully digitalized and/or given additional diuretic, and the response observed closely: a) if cardiac failure continues, despite adequate digitalization and diuretic therapy, propranolol therapy should be withdrawn (gradually, if possible); b) if tachyarrhythmia is being controlled, patients should be maintained on combined therapy and the patient closely followed until threat of cardiac failure is over.
There have been reports of exacerbation of angina and, in some cases, myocardial infarction following abrupt discontinuation of propranolol therapy. Therefore, when discontinuance of propranolol is planned, the dosage should be gradually reduced and the patient should be carefully monitored. In addition, when propranolol is prescribed for angina pectoris, the patient should be cautioned against interruption or cessation of therapy without the physician’s advice. If propranolol therapy is interrupted and exacerbation of angina occurs, it usually is advisable to reinstitute propranolol therapy and take other measures appropriate for the management of unstable angina pectoris. Since coronary artery disease may be unrecognized, it may be prudent to follow the above advice in patients considered at risk of having occult atherosclerotic heart disease, who are given propranolol for other indications.
PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD, IN GENERAL, NOT RECEIVE BETA-BLOCKERS. Propranolol should be administered with caution since it may block bronchodilation produced by endogenous and exogenous catecholamine stimulation of beta-receptors.
The necessity or desirability of withdrawal of beta-blocking therapy prior to major surgery is controversial. It should be noted, however, that the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.
Propranolol, like other beta-blockers, is a competitive inhibitor of beta-receptor agonists, and its effects can be reversed by administration of such agents, e.g., dobutamine or isoproterenol. However, such patients may be subject to protracted severe hypotension. Difficulty in starting and maintaining the heartbeat has also been reported with beta-blockers.
Beta-adrenergic blockade may prevent the appearance of certain premonitory signs and symptoms (pulse rate and pressure changes) of acute hypoglycemia in labile insulin-dependent diabetes. In these patients, it may be more difficult to adjust the dosage of insulin. Hypoglycemic attack may be accompanied by a precipitous elevation of blood pressure in patients on propranolol.
Propranolol therapy, particularly in infants and children, diabetic or not, has been associated with hypoglycemia especially during fasting as in preparation for surgery. Hypoglycemia also has been found after this type of drug therapy and prolonged physical exertion and has occurred in renal insufficiency, both during dialysis and sporadically, in patients on propranolol.
Acute increases in blood pressure have occurred after insulin-induced hypoglycemia in patients on propranolol.
Beta-blockade may mask certain clinical signs of hyperthyroidism. Therefore, abrupt withdrawal of propranolol may be followed by an exacerbation of symptoms of hyperthyroidism, including thyroid storm. Propranolol may change thyroid-function tests, increasing T4 and reverse T3, and decreasing T3.
Several cases have been reported in which, after propranolol, the tachycardia was replaced by a severe bradycardia requiring a demand pacemaker. In one case this resulted after an initial dose of 5 mg propranolol.
Cutaneous reactions, including Stevens-Johnson Syndrome, toxic epidermal necrolysis, exfoliative dermatitis, erythema multiforme, and urticaria, have been reported with use of propranolol (see ADVERSE REACTIONS).
Thiazides should be used with caution in severe renal disease. In patients with renal disease, thiazides may precipitate azotemia. In patients with impaired renal function, cumulative effects of the drug may develop.
Thiazides should also be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.
Thiazides may add to or potentiate the action of other antihypertensive drugs. Potentiation occurs with ganglionic or peripheral adrenergic-blocking drugs.
Sensitivity reactions may occur in patients with a history of allergy or bronchial asthma. The possibility of exacerbation or activation of systemic lupus erythematosus has been reported.
Propranolol should be used with caution in patients with impaired hepatic or renal function. Propranolol hydrochloride and hydrochlorothiazide tablets are not indicated for the treatment of hypertensive emergencies.
While taking beta-blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction.
All patients receiving thiazide therapy should be observed for clinical signs of fluid or electrolyte imbalance, namely hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral fluids. Medication such as digitalis may also influence serum electrolytes. Warning signs, irrespective of cause, are: dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.
Hypokalemia may develop, especially with brisk diuresis or when severe cirrhosis is present.
Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia can sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability).
Hypokalemia may be avoided or treated by use of potassium supplements or foods with a high potassium content.
Any chloride deficit is generally mild, and usually does not require specific treatment except under extraordinary circumstances (as in liver or renal disease). Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction rather than administration of salt, except in rare instances when the hyponatremia is life threatening. In actual salt depletion, appropriate replacement is the therapy of choice.
Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy.
Diabetes mellitus which has been latent may become manifest during thiazide administration.
The antihypertensive effects of the drug may be enhanced in the postsympathectomy patient.
If progressive renal impairment becomes evident, consider withholding or discontinuing diuretic therapy.
Calcium excretion is decreased by thiazides. Pathologic changes in the parathyroid gland with hypercalcemia and hypophosphatemia have been observed in a few patients on prolonged thiazide therapy. The common complications of hyperparathyroidism, such as renal lithiasis, bone resorption, and peptic ulceration, have not been seen.
Beta-adrenoreceptor blockade can cause reduction of intraocular pressure. Patients should be told that propranolol hydrochloride and hydrochlorothiazide may interfere with the glaucoma screening test. Withdrawal may lead to a return of increased intraocular pressure.
Elevated blood urea levels in patients with severe heart disease, elevated serum transaminase, alkaline phosphatase, lactate dehydrogenase.
Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals.
Patients receiving catecholamine-depleting drugs such as reserpine should be closely observed if propranolol hydrochloride and hydrochlorothiazide is administered. The added catecholamine-blocking action may produce an excessive reduction of resting sympathetic nervous activity, which may result in hypotension, marked bradycardia, vertigo, syncopal attacks, or orthostatic hypotension.
Caution should be exercised when patients receiving a beta-blocker are administered a calcium-channel blocking drug, especially intravenous verapamil, for both agents may depress myocardial contractility or atrioventricular conduction. On rare occasions, the concomitant intravenous use of a beta-blocker and verapamil has resulted in serious adverse reactions, especially in patients with severe cardiomyopathy, congestive heart failure, or recent myocardial infarction.
Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.
Blunting of the antihypertensive effect of beta-adrenoceptor blocking agents by nonsteroidal anti-inflammatory drugs has been reported.
Hypotension and cardiac arrest have been reported with the concomitant use of propranolol and haloperidol.
Aluminum hydroxide gel greatly reduces intestinal absorption of propranolol.
Alcohol, when used concomitantly with propranolol, may increase plasma levels of propranolol.
Phenytoin, phenobarbitone, and rifampin accelerate propranolol clearance.
Chlorpromazine, when used concomitantly with propranolol, results in increased plasma levels of both drugs.
Antipyrine and lidocaine have reduced clearance when used concomitantly with propranolol.
Thyroxine may result in a lower than expected T3 concentration when used concomitantly with propranolol.
Cimetidine decreases the hepatic metabolism of propranolol, delaying elimination and increasing blood levels.
Theophylline clearance is reduced when used concomitantly with propranolol.
Thiazide drugs may increase the responsiveness to tubocurarine.
Thiazides may decrease arterial responsiveness to norepinephrine. This diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use.
Insulin requirements in diabetic patients may be increased, decreased, or unchanged.
Hypokalemia may develop during concomitant use of corticosteroids or ACTH.
Thiazides may decrease serum PBI levels without signs of thyroid disturbance.
Thiazides should be discontinued before carrying out tests for parathyroid function (see PRECAUTIONS: General).
Combinations of Propranolol and Hydrochlorothiazide have not been evaluated for carcinogenic or mutagenic potential or for potential to adversely affect fertility.
In dietary administration studies in which mice and rats were treated with propranolol for up to 18 months at doses of up to 150 mg/kg/day, there was no evidence of drug-related tumorigenesis. In a study in which both male and female rats were exposed to propranolol in their diets at concentrations of up to 0.05%, from 60 days prior to mating and throughout pregnancy and lactation for two generations, there were no effects on fertility. Based on differing results from Ames Tests performed by different laboratories, there is equivocal evidence for a genotoxic effect of propranolol in bacteria (S. typhimurium strain TA 1538).
Two-year feeding studies in mice and rats conducted under the auspices of the National Toxicology Program (NTP) uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in female mice (at doses of up to approximately 600 mg/kg/day) or in male and female rats (at doses of up to approximately 100 mg/kg/day). The NTP, however, found equivocal evidence for hepatocarcinogenicity in male mice.
Hydrochlorothiazide was not genotoxic in vitro in the Ames bacterial mutagen assay (S. typhimurium strains TA 98, TA 100, TA 1535, TA 1537 and TA 1538) or in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations. Nor was it genotoxic in vivo in assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained in the in vitro CHO Sister Chromatid Exchange (clastogenicity), Mouse Lymphoma Cell (mutagenicity) and Aspergillus nidulans non-disjunction assays.
Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via their diet, to doses of up to 100 mg/kg and 4 mg/kg, respectively, prior to mating and throughout gestation.
Combinations of Propranolol and Hydrochlorothiazide have not been evaluated for effects on pregnancy in animals. Nor are there adequate and well controlled studies of propranolol, hydrochlorothiazide or the combination in pregnant women. Propranolol and Hydrochlorothiazide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
In a series of reproduction and developmental toxicology studies, propranolol was given to rats by gavage or in the diet throughout pregnancy and lactation. At doses of 150 mg/kg/day (> 30 times the dose of propranolol contained in the maximum recommended human daily dose of propranolol hydrochloride and hydrochlorothiazide), but not at doses of 80 mg/kg/day, treatment was associated with embryotoxicity (reduced litter size and increased resorption sites) as well as neonatal toxicity (deaths). Propranolol also was administered (in the feed) to rabbits (throughout pregnancy and lactation) at doses as high as 150 mg/kg/day (> 45 times the dose of propranolol contained in the maximum recommended daily human dose of propranolol hydrochloride and hydrochlorothiazide). No evidence of embryo or neonatal toxicity was noted.
Intrauterine growth retardation, small placentas, and congenital abnormalities have been reported in human neonates whose mothers received propranolol during pregnancy. Neonates whose mothers received propranolol at parturition have exhibited bradycardia, hypoglycemia and/or respiratory depression. Adequate facilities for monitoring these infants at birth should be available.
Studies in which hydrochlorothiazide was orally administered to pregnant mice and rats at doses of up to 3000 and 1000 mg/kg/day, respectively, provided no evidence of harm to the fetus.
Thiazides cross the placental barrier and appear in cord blood. The use of thiazides in pregnant women requires that the anticipated benefit be weighed against possible hazards to the fetus. These hazards include fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in the adult.
Propranolol is excreted in human milk. Caution should be exercised when propranolol hydrochloride and hydrochlorothiazide is administered to a nursing woman.
Thiazides appear in breast milk. If the use of the drug is deemed essential, the patient should stop nursing.
Safety and effectiveness in pediatric patients have not been established.
Clinical studies of propranolol hydrochloride and hydrochlorothiazide did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.
In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
The following adverse reactions have been observed, but there is not enough systematic collection of data to support an estimate of their frequency. Within each category, adverse reactions are listed in decreasing order of severity. Although many side effects are mild and transient, some require discontinuation of therapy.
Cardiovascular: Congestive heart failure; hypotension; intensification of AV block; bradycardia; thrombocytopenic purpura; arterial insufficiency, usually of the Raynaud type; paresthesia of hands.
Central Nervous System: Reversible mental depression progressing to catatonia; mental depression manifested by insomnia, lassitude, weakness, fatigue; an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability, slightly clouded sensorium, decreased performance on neuropsychometrics; hallucinations; visual disturbances; vivid dreams; light-headedness. Total daily doses above 160 mg (when administered as divided doses of greater than 80 mg each) may be associated with an increased incidence of fatigue, lethargy, and vivid dreams.
Gastrointestinal: Mesenteric arterial thrombosis; ischemic colitis; nausea, vomiting, epigastric distress, abdominal cramping, diarrhea, constipation.
Allergic: Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions; laryngospasm and respiratory distress; pharyngitis and agranulocytosis; fever combined with aching and sore throat; erythematous rash.
Respiratory: Bronchospasm.
Hematologic: Agranulocytosis; non-thrombocytopenic purpura; thrombocytopenic purpura.
Autoimmune: In extremely rare instances, systemic lupus erythematosus has been reported.
Miscellaneous: Male impotence. Alopecia, LE-like reactions, psoriasiform rashes, dry eyes, and Peyronie’s disease have been reported rarely. Oculomucocutaneous reactions involving the skin, serous membranes, and conjunctivae reported for a beta-blocker (practolol) have not been associated with propranolol.
Skin: Stevens-Johnson Syndrome; toxic epidermal necrolysis; exfoliative dermatitis; erythema multiforme; urticaria.
Cardiovascular: Orthostatic hypotension (may be aggravated by alcohol, barbiturates or narcotics).
Central Nervous System: Dizziness, vertigo, headache, xanthopsia, paresthesias.
Gastrointestinal: Pancreatitis; jaundice (intrahepatic cholestatic jaundice); sialadenitis; anorexia, nausea, vomiting, gastric irritation, cramping, diarrhea, constipation.
Hypersensitivity: Anaphylactic reactions; necrotizing angiitis (vasculitis, cutaneous vasculitis); respiratory distress including pneumonitis; fever; urticaria, rash, purpura, photosensitivity.
Hematologic: Aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia.
Skin: Erythema multiforme including Stevens-Johnson Syndrome, exfoliative dermatitis including toxic epidermal necrolysis.
Miscellaneous: Hyperglycemia, glycosuria; hyperuricemia; muscle spasm; weakness; restlessness; transient blurred vision.
Whenever adverse reactions are moderate or severe, thiazide dosage should be reduced or therapy withdrawn.
The propranolol hydrochloride component may cause bradycardia, cardiac failure, hypotension, or bronchospasm. Propranolol is not significantly dialyzable.
The hydrochlorothiazide component can be expected to cause diuresis. Lethargy of varying degree may appear and may progress to coma within a few hours, with minimal depression of respiration and cardiovascular function, and in the absence of significant serum electrolyte changes or dehydration. The mechanism of central nervous system depression with thiazide overdosage is unknown. Gastrointestinal irritation and hypermotility can occur, temporary elevation of BUN has been reported, and serum electrolyte changes could occur, especially in patients with impairment of renal function.
The oral LD50 dosages in rats and mice for propranolol, hydrochlorothiazide and combined propranolol/hydrochlorothiazide (40/25, 80/25) are 364 to 533 mg/kg, greater than 2750 to 5000 mg/kg, and 538 to 845 mg/kg, respectively.
The following measures should be employed:
General: If ingestion is, or may have been, recent, evacuate gastric contents, taking care to prevent pulmonary aspiration.
Bradycardia: Administer atropine (0.25 mg to 1 mg). If there is no response to vagal blockade, administer isoproterenol cautiously.
Cardiac Failure: Digitalization and diuretics.
Hypotension: Vasopressors, e.g., levarterenol or epinephrine.
Bronchospasm: Administer isoproterenol and aminophylline.
Stupor or Coma: Administer supportive therapy as clinically warranted.
Gastrointestinal Effects: Though usually of short duration, these may require symptomatic treatment.
Abnormalities in BUN and/or Serum Electrolytes:Monitor serum electrolyte levels and renal function; institute supportive measures as required individually to maintain hydration, electrolyte balance, respiration, and cardiovascular-renal function.
The dosage must be determined by individual titration.
Hydrochlorothiazide can be given at doses of 12.5 to 50 mg per day when used alone. The initial dose of propranolol is 80 mg daily, and it may be increased gradually until optimal blood pressure control is achieved. The usual effective dose when used alone is 160 to 480 mg per day.
One propranolol hydrochloride and hydrochlorothiazide tablet twice daily can be used to administer up to 160 mg of propranolol and 50 mg of hydrochlorothiazide. For doses of propranolol greater than 160 mg the combination products are not appropriate, because their use would lead to an excessive dose of the thiazide component.
When necessary, another antihypertensive agent may be added gradually beginning with 50 percent of the usual recommended starting dose to avoid an excessive fall in blood pressure.
Propranolol Hydrochloride and Hydrochlorothiazide Tablets, USP are available in the following combinations:
The 40 mg/25 mg tablets contain 40 mg of propranolol hydrochloride, USP and 25 mg of hydrochlorothiazide, USP. Each white round scored tablet is debossed with MYLAN over 731 on one side of the tablet and scored on the other side. They are available as follows:
NDC 0378-0731-01
bottles of 100 tablets
The 80 mg/25 mg tablets contain 80 mg of propranolol hydrochloride, USP and 25 mg of hydrochlorothiazide, USP. Each white round scored tablet is debossed with MYLAN over 347 on one side of the tablet and scored on the other side. They are available as follows:
NDC 0378-0347-01
bottles of 100 tablets
Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]
Protect from moisture, freezing, and excessive heat.
Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505
REVISED JUNE 2010
PRAN/HCTZ:R18
PRINCIPAL DISPLAY PANEL - 40 mg/25 mg
NDC 0378-0731-01
PROPRANOLOL HCl and
HYDROCHLOROTHIAZIDE
TABLETS, USP
40 mg/25 mg
100 TABLETS (Rx only)
Each tablet contains:
Propranolol hydrochloride,
USP . . . . . . . . . . . 40 mg
Hydrochlorothiazide,
USP . . . . . . . . . . . 25 mg
Dispense in a tight, light-resistant
container as defined in the USP
using a child-resistant closure.
Keep container tightly closed.
Keep this and all medication
out of the reach of children.
Store at 20° to 25°C (68° to 77°F).
[See USP Controlled Room
Temperature.]
Protect from moisture, freezing,
and excessive heat.
Usual Adult Dosage: See accom-
panying prescribing information.
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505
RM0731A6
PRINCIPAL DISPLAY PANEL - 80 mg/25 mg
NDC 0378-0347-01
PROPRANOLOL HCl and
HYDROCHLOROTHIAZIDE
TABLETS, USP
80 mg/25 mg
100 TABLETS (Rx only)
Each tablet contains:
Propranolol hydrochloride,
USP . . . . . . . . . . . 80 mg
Hydrochlorothiazide,
USP . . . . . . . . . . . 25 mg
Dispense in a tight, light-resistant
container as defined in the USP
using a child-resistant closure.
Keep container tightly closed.
Keep this and all medication
out of the reach of children.
Store at 20° to 25°C (68° to 77°F).
[See USP Controlled Room
Temperature.]
Protect from moisture, freezing,
and excessive heat.
Usual Adult Dosage: See accom-
panying prescribing information.
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505
RM0347A7
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| Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date |
| ANDA | ANDA070947 | 08/19/2010 | |
| PROPRANOLOL HYDROCHLORIDE AND HYDROCHLOROTHIAZIDE propranolol hydrochloride and hydrochlorothiazide tablet | ||||||||||||||||||||
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| Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date |
| ANDA | ANDA070947 | 08/19/2010 | |
| Labeler - Mylan Pharmaceuticals Inc. (059295980) |
| Registrant - Mylan Pharmaceuticals Inc. (059295980) |
Generic Name: chlorzoxazone (Oral route)
klor-ZOX-a-zone
In the U.S.
Available Dosage Forms:
Therapeutic Class: Skeletal Muscle Relaxant, Centrally Acting
Chlorzoxazone is used to relax certain muscles in your body and relieve the discomfort caused by acute (short-term), painful muscle or bone conditions. However, this medicine does not take the place of rest, exercise, physical therapy, or other treatments that your doctor may recommend for your medical condition.
Chlorzoxazone is a skeletal muscle relaxant. It acts on the central nervous system (CNS) to relax muscles.
This medicine is available only with your doctor's prescription.
In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:
Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.
No information is available on the relationship of age to the effects of chlorzoxazone in the pediatric population. Safety and efficacy have not been established.
No information is available on the relationship of age to the effects of chlorzoxazone in geriatric patients. However, elderly patients are more likely to have age-related liver problems, which may require caution in patients receiving chlorzoxazone.
There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.
Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.
Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.
Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.
The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:
This section provides information on the proper use of a number of products that contain chlorzoxazone. It may not be specific to Parafon Forte DSC. Please read with care.
The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.
The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.
If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.
Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.
Keep out of the reach of children.
Do not keep outdated medicine or medicine no longer needed.
Ask your healthcare professional how you should dispose of any medicine you do not use.
It is very important that your doctor check your progress at regular visits to make sure that this medicine is working properly and to check for unwanted effects.
Liver problems may occur while you are using this medicine. Stop using this medicine and check with your doctor right away if you are having more than one of these symptoms: abdominal pain or tenderness; clay-colored stools; dark urine; decreased appetite; fever; headache; itching; loss of appetite; nausea and vomiting; skin rash; swelling of the feet or lower legs; unusual tiredness or weakness; or yellow eyes or skin.
This medicine will add to the effects of alcohol and other CNS depressants (medicines that make you drowsy or less alert). Some examples of CNS depressants are antihistamines or medicine for hay fever, allergies, or colds; sedatives, tranquilizers, or sleeping medicine; prescription pain medicine or narcotics; barbiturates; medicine for seizures; or anesthetics, including some dental anesthetics. Check with your medical doctor or dentist before taking any of these medicines while you are taking chlorzoxazone.
Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.
Check with your doctor immediately if any of the following side effects occur:
Get emergency help immediately if any of the following symptoms of overdose occur:
Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:
Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.
Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.
See also: Parafon Forte DSC side effects (in more detail)
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Prolastin-C is a preparation of alpha1-proteinase inhibitor that is indicated for chronic augmentation and maintenance therapy in adults with emphysema due to deficiency of alpha1-proteinase inhibitor (Alpha1-PI, alpha1-antitrypsin deficiency). The effect of augmentation therapy with any Alpha1-PI product on pulmonary exacerbations and on the progression of emphysema in alpha1-antitrypsin deficiency has not been demonstrated in adequately powered, randomized, controlled, clinical trials. Prolastin-C is not indicated as therapy for lung disease in patients in whom severe Alpha1-PI deficiency has not been established.
For intravenous use only.
The recommended dose of Prolastin-C is 60 mg/kg body weight administered once weekly. Dose ranging studies using efficacy endpoints have not been performed with any alpha1-proteinase inhibitor product. Each vial of Prolastin-C contains the labeled amount of functionally active Alpha1-PI in milligrams (as determined by the capacity to neutralize porcine pancreatic elastase) as stated on the label.
Prolastin-C should be given intravenously at a rate of approximately 0.08 mL/kg/min as determined by the response and comfort of the patient. The recommended dosage of 60 mg/kg takes approximately 15 minutes to infuse.
Each product package contains one Prolastin-C single use vial, one 20 mL vial of Sterile Water for Injection (diluent), one color-coded sterile transfer needle, and one sterile filter needle. Administer within three hours after reconstitution.
Use aseptic technique.
Described here is one acceptable method of reconstitution. The product could also be reconstituted with other appropriate devices according to the manufacturer’s accepted procedure.
Prolastin-C should be stored at temperatures not to exceed 25°C (77°F) for the period indicated by the expiration date on its label.
Freezing should be avoided as breakage of the diluent bottle might occur.
Prolastin-C is supplied in 1000 mg single use vials with a separate 20 mL vial of Sterile Water for Injection, USP.
Prolastin-C is contraindicated in IgA deficient patients with antibodies against IgA, due to the risk of severe hypersensitivity.
Hypersensitivity reactions may occur. Should evidence of an acute hypersensitivity reaction be observed, the infusion should be stopped promptly and appropriate countermeasures and supportive therapy should be administered. (See Patient Counseling Information [17])
Prolastin-C may contain trace amounts of IgA. Patients with known antibodies to IgA, which can be present in patients with selective or severe IgA deficiency, have a greater risk of developing potentially severe hypersensitivity and anaphylactic reactions. Prolastin-C is contraindicated in patients with antibodies against IgA.
Products made from human plasma may carry a risk of transmitting infectious agents, e.g., viruses, and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. In each of 2 randomized, double-blind studies in which the predecessor product, PROLASTIN® (Alpha1-Proteinase Inhibitor [Human]), was compared to other Alpha1 products, there was a single case of parvovirus B19 seroconversion in the PROLASTIN arms of each trial. In each case, it could not be determined whether parvovirus B19 had been acquired from PROLASTIN or from the community. However, during clinical studies with Prolastin-C, there were no reported treatment emergent cases of hepatitis B, hepatitis C, HIV or parvovirus B19 viral infections. Furthermore, the Prolastin-C process incorporates additional plasma safety and virus reduction measures that minimize the residual risk of virus transmission (See Description [11]).
The physician should discuss the risks and benefits of this product with the patient, before prescribing or administering it to a patient. (See Patient Counseling Information [17]). All infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Talecris Biotherapeutics, Inc. [1-800-520-2807].
The most serious adverse reaction observed during clinical studies with Prolastin-C was an abdominal and extremity rash in one subject. The rash resolved subsequent to outpatient treatment with antihistamines and steroids. Two instances of a less severe, pruritic abdominal rash were observed upon rechallenge despite continued antihistamine and steroid treatment, which led to withdrawal of the subject from the trial.
The most common drug-related adverse reactions observed at a rate of ≥ 1% in subjects receiving Prolastin-C were chills, malaise, headache, rash, hot flush and pruritus.
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in practice.
Two separate clinical studies were conducted with Prolastin-C: (1) A 20 week, open-label, single arm safety study in 38 subjects, and (2) A 16 week, randomized, double-blind, crossover pharmacokinetic comparability study vs. PROLASTIN in 24 subjects, followed by an 8 week open-label treatment with Prolastin-C. Thus, 62 subjects were exposed to Prolastin-C in clinical trials.
Adverse reactions considered drug related by the investigators occurring in 1.6% of subjects (one subject each) treated with Prolastin-C were malaise, headache, rash, hot flush, and pruritus. Drug related chills occurred in 3.2% (2 subjects) of Prolastin-C subjects.
Adverse events occurring irrespective of causality in ≥ 5% of subjects in the first 8 weeks of treatment are shown in Table 1. Adverse events which occurred in the first 8 weeks of treatment are shown in the table in order to control for the differing treatment durations of the safety and PK studies (20 weeks vs. two 8 week periods).
| PROLASTIN® -C No. of subjects: 62 | PROLASTIN® No. of subjects: 24 | |
|---|---|---|
| Adverse Event | No. of subjects with AE (percentage of all subjects) | No. of subjects with AE (percentage of all subjects) |
| Source: studies 11815 and 11816 | ||
| Nausea | 4 (6.5%) | 0 |
| Urinary Tract Infection | 4 (6.5%) | 0 |
| Headache | 3 (4.8%) | 2 (8.3%) |
| Arthralgia | 2 (3.2%) | 2 (8.3%) |
Table 2 below displays the overall adverse rate (> 0.5%), irrespective of causality, as a percentage of infusions received.
| PROLASTIN® -C No. of infusions: 1132 | PROLASTIN® No. of infusions: 192 | |
|---|---|---|
| Adverse Event | No. of AE (percentage of all infusions) | No. of AE (percentage of all infusions) |
| Source: studies 11815 and 11816 | ||
| Upper respiratory tract infection | 9 (0.8%) | 1 (0.5%) |
| Urinary tract infection | 8 (0.7%) | 0 |
| Nausea | 7 (0.6%) | 0 |
| Headache | 4 (0.4%) | 3 (1.6%) |
| Arthralgia | 2 (0.2%) | 2 (1.0%) |
Table 3 below displays the overall rates of adverse events (≥ 5%), in the first eight weeks of treatment, that began during or within 72 hours of the end of an infusion of Prolastin-C or PROLASTIN.
| PROLASTIN® -C No. of subjects: 62 | PROLASTIN® No. of subjects: 24 | |
|---|---|---|
| Adverse Event | No. of subjects with AE (percentage of all subjects) | No. of subjects with AE (percentage of all subjects) |
| Source: studies 11815 and 11816 | ||
| Urinary Tract Infection | 4 (6.5%) | 0 |
| Headache | 3 (4.8%) | 2 (8.3%) |
Ten exacerbations of chronic obstructive pulmonary disease were reported by 8 subjects in the 24 week pharmacokinetic crossover study. During the 16 week double-blind crossover phase, 4 subjects (17%) had a total of 4 exacerbations during Prolastin-C treatment and 4 subjects (17%) had a total of 4 exacerbations during PROLASTIN treatment. Two additional exacerbations in 2 subjects (8%) occurred during the 8 week open label treatment period with Prolastin-C. The overall rate of pulmonary exacerbations during treatment with either product was 0.9 exacerbations per subject-year.
Because postmarketing reporting of adverse reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate the frequency of these reactions or establish a causal relationship to product exposure.
The following adverse reactions have been identified and reported during the post marketing use of the predecessor product, PROLASTIN:
Prolastin-C should be given alone, without mixing with other agents or diluting solutions.
Pregnancy Category C. Animal reproduction studies have not been conducted with Prolastin-C. It is not known whether Prolastin-C can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Prolastin-C should be given to a pregnant woman only if clearly needed.
It is not known whether Prolastin-C is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Prolastin-C is administered to a nursing woman.
Safety and effectiveness in the pediatric population have not been established.
Clinical studies of Prolastin-C did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. As for all patients, dosing for geriatric patients should be appropriate to their overall situation.
Alpha1-Proteinase Inhibitor (Human), Prolastin-C, is a sterile, stable, lyophilized preparation of purified human alpha1-proteinase inhibitor (Alpha1-PI), also known as alpha1-antitrypsin. Prolastin-C is intended for use in therapy for patients with emphysema due to congenital alpha1-antitrypsin deficiency. Prolastin-C is produced through modifications of the PROLASTIN process that result in improved product purity and a higher concentration of the same active substance, Alpha1-PI, in the reconstituted product.
Prolastin-C is supplied as a sterile, white to beige, lyophilized powder. The specific activity of Prolastin-C is ≥ 0.7 mg functional Alpha1-PI per mg of total protein. Prolastin-C has a purity of ≥ 90% Alpha1-PI. Each vial contains approximately 1000 mg of functionally active Alpha1-PI. When reconstituted with 20 mL of Sterile Water for Injection, USP, Prolastin-C has a pH of 6.6–7.4, a sodium content of 100–210 mM, a chloride content of 60–180 mM and a sodium phosphate content of 15–25 mM.
Each vial of Prolastin-C contains the labeled amount of functionally active Alpha1-PI in milligrams per vial (mg/vial), as determined by capacity to neutralize porcine pancreatic elastase. Prolastin-C contains no preservative and must be administered by the intravenous route.
Prolastin-C is prepared by cold ethanol fractionation of pooled human plasma based on modifications and refinements of the Cohn method (1) using purification by polyethylene glycol (PEG) precipitation, anion exchange chromatography, and cation exchange chromatography. All source plasma used in the manufacture of this product is non-reactive (negative) by FDA-licensed serological test methods for hepatitis B surface antigen (HBsAg) and antibodies to hepatitis C virus (HCV) and human immunodeficiency virus types 1 and 2 and negative by FDA-licensed Nucleic Acid Technologies (NAT) for HCV and human immunodeficiency virus type 1 (HIV-1). In addition, all source plasma is negative for hepatitis B virus (HBV) by either an FDA-licensed or investigational NAT assay. The goal of the investigational HBV NAT test is to detect low levels of viral nucleic acid; however, the significance of a negative result for the investigational HBV NAT test has not been established. By in-process NAT, all source plasma is negative for hepatitis A virus (HAV). As a final plasma safety step, all plasma manufacturing pools are tested by serological test methods and NAT.
To provide additional assurance of the virus safety profile of Prolastin-C, in vitro studies have been conducted to validate the capacity of the manufacturing process to reduce the infectious titer of a wide range of viruses with diverse physicochemical properties. These studies evaluated the inactivation/removal of clinically relevant viruses, including human immunodeficiency virus type 1 (HIV-1) and hepatitis A virus (HAV), as well as the following model viruses: bovine viral diarrhea virus (BVDV), a surrogate for hepatitis C virus; pseudorabies virus (PRV), a surrogate for large enveloped DNA viruses (e.g., herpes viruses); vesicular stomatitis virus (VSV), a model for enveloped viruses; reovirus type 3 (Reo3), a non-specific model for non-enveloped viruses; and porcine parvovirus (PPV), a model for human parvovirus B19.
The Prolastin-C manufacturing process has several steps (Cold Ethanol Fractionation, PEG Precipitation, and Depth Filtration) that are important for purifying Alpha1-PI as well as removing potential virus contaminants. Two additional steps, Solvent/Detergent Treatment and 15 nm Virus Removal Nanofiltration, are included in the process as dedicated pathogen reduction steps. The Solvent/Detergent Treatment step effectively inactivates enveloped viruses (such as HIV-1, VSV, HBV, and HCV). The 15 nm Virus Removal Nanofiltration step has been implemented to reduce the risk of transmission of enveloped and non-enveloped viruses as small as 18 nm. The table below presents the virus reduction capacity of each process step and the accumulated virus reduction for the process as determined in viral validation studies in which virus was deliberately added to a process model in order to study virus reduction. In addition, the Solvent/Detergent Treatment step inactivates ≥ 5.4 log10 of West Nile virus, a clinically relevant enveloped virus. Studies have demonstrated that each step provides robust virus reduction across the production range for key operating parameters.
| Process Step | Enveloped Viruses | Non-enveloped Viruses | |||||
|---|---|---|---|---|---|---|---|
| HIV-1 | BVDV | PRV | VSV | Reo3 | HAV | PPV | |
| |||||||
| Cold Ethanol Fractionation | 3.4 | 3.5 | 3.9 | ND* | ≥2.1 | 1.4 | 1.0 |
| PEG Precipitation | 4.3 | 2.8 | 3.3 | ND | 3.3 | 3.0 | 3.2 |
| Depth Filtration | ≥4.7 | 4.0 | ≥4.8 | ND | ≥4.0 | ≥2.8 | ≥4.4 |
| Solvent/Detergent Treatment | ≥6.2 | ≥4.6 | ≥4.3 | 5.1 | NA† | NA | NA |
| 15 nm Virus Removal Nanofiltration | ≥6.9 | ≥4.7 | ≥5.2 | ≥5.1 | ≥4.3 | ≥5.5 | 4.2 |
| Accumulated Virus Reduction | ≥25.5 | ≥19.6 | ≥21.5 | ≥10.2 | ≥13.7 | ≥12.7 | ≥12.8 |
Additionally, the manufacturing process was investigated for its capacity to decrease the infectivity of an experimental agent of transmissible spongiform encephalopathy (TSE), considered as a model for the variant Creutzfeldt-Jakob disease (vCJD) and Creutzfeldt-Jakob disease (CJD) agents. Studies of the Prolastin-C manufacturing process demonstrate that a minimum of 6 log10 reduction of TSE infectivity is achieved. These studies provide reasonable assurance that low levels of vCJD/CJD agent infectivity, if present in the starting material, would be removed.
Alpha1-proteinase inhibitor (Alpha1-PI) deficiency (AAT deficiency) is an autosomal, co-dominant, hereditary disorder characterized by low serum and lung levels of Alpha1-PI (2-5). Smoking is an important risk factor for the development of emphysema in patients with alpha1-proteinase inhibitor deficiency (6). Because emphysema affects many, but not all individuals with the more severe genetic variants of Alpha1-PI deficiency, augmentation therapy with Alpha1-Proteinase Inhibitor (Human) is indicated only in patients with severe Alpha1-PI deficiency who have clinically evident emphysema.
Only some Alpha1-PI alleles are associated with clinically apparent AAT deficiency (7,8). Approximately 95% of all severely AAT deficient patients are homozygous for the PiZ allele (8). Individuals with the PiZZ variant typically have serum Alpha1-PI levels less than 35% of the average normal level (2,4). Individuals with the Pi(null)(null) variant have undetectable Alpha1-PI protein in their serum (2,3). Individuals with these low serum Alpha1-PI levels, i.e., less than 11 µM, have a markedly increased risk for developing emphysema over their lifetimes. In addition, PiSZ individuals, whose serum Alpha1-PI levels range from approximately 9 to 23 µM (9), are considered to have moderately increased risk for developing emphysema, regardless of whether their serum Alpha1-PI levels are above or below 11 µM.
Augmenting the levels of functional protease inhibitor by intravenous infusion is an approach to therapy for patients with AAT deficiency. The intended theoretical goal is to provide protection to the lower respiratory tract by correcting the imbalance between neutrophil elastase and protease inhibitors. Whether augmentation therapy with any Alpha1-PI product actually protects the lower respiratory tract from progressive emphysematous changes has not been demonstrated in adequately powered, randomized controlled, clinical trials. Although the maintenance of blood serum levels of Alpha1-PI (antigenically measured) above 11 µM has been historically postulated to provide therapeutically relevant anti-neutrophil elastase protection (10), this has not been proven. Individuals with severe Alpha1-PI deficiency have been shown to have increased neutrophil and neutrophil elastase concentrations in lung epithelial lining fluid compared to normal PiMM individuals, and some PiSZ individuals with Alpha1-PI above 11 µM have emphysema attributed to Alpha1-PI deficiency. These observations underscore the uncertainty regarding the appropriate therapeutic target serum level of Alpha1-PI during augmentation therapy.
The pathogenesis of emphysema is understood to evolve as described in the “protease-antiprotease imbalance” model (11). Alpha1-PI is understood to be the primary antiprotease in the lower respiratory tract, where it inhibits neutrophil elastase (NE) (12). Normal healthy individuals produce sufficient Alpha1-PI to control the NE produced by activated neutrophils and are thus able to prevent inappropriate proteolysis of the lung tissue by NE. Conditions that increase neutrophil accumulation and activation in the lung, such as respiratory infection and smoking, will in turn increase levels of NE. However, individuals who are severely deficient in endogenous Alpha1-PI are unable to maintain an appropriate antiprotease defense, and, in addition, they have been shown to have increased lung epithelial lining fluid neutrophil and NE concentrations. Because of these factors, many (but not all) individuals who are severely deficient in endogenous Alpha1-PI are subject to more rapid proteolysis of the alveolar walls leading to chronic lung disease. PROLASTIN®-C (Alpha1-Proteinase Inhibitor [Human]) serves as Alpha1-PI augmentation therapy in the patient population with severe Alpha1-PI deficiency and emphysema, acting to increase and maintain serum and lung epithelial lining fluid levels of Alpha1-PI.
Chronic augmentation therapy with the predecessor product, PROLASTIN® (Alpha1-Proteinase Inhibitor [Human]), administered weekly at a dose of 60 mg/kg body weight, results in significantly increased levels of Alpha1-PI and functional anti-neutrophil elastase capacity in the epithelial lining fluid of the lower respiratory tract of the lung, as compared to levels prior to commencing therapy with PROLASTIN (11-13). However, the clinical benefit of the increased levels at the recommended dose has not been demonstrated in adequately powered, randomized, controlled clinical trials for any Alpha1-PI product.
The pharmacokinetic (PK) study was a randomized, double-blind, crossover trial comparing Prolastin-C to PROLASTIN conducted in 24 adult subjects age 40 to 72 with severe AAT deficiency. Ten subjects were male and 14 subjects were female. Twelve subjects were randomized to each treatment sequence. All but one subject had the PiZZ genotype and the remaining subject had PiSZ. All subjects had received prior Alpha1-PI therapy with PROLASTIN for at least 1 month.
Study subjects were randomly assigned to receive either 60 mg/kg body weight of functional Prolastin-C or PROLASTIN weekly by IV infusion during the first 8 week treatment period. Following the last dose in the first 8-week treatment period, subjects underwent serial blood sampling for PK analysis and then crossed over to the alternate treatment for the second 8-week treatment period. Following the last treatment in the second 8-week treatment period, subjects underwent serial blood sampling for PK analysis. In addition, blood samples were drawn for trough levels before infusion at Weeks 6, 7, and 8, as well as before infusion at Weeks 14, 15, and 16.
In the 8-week open-label treatment phase that followed the crossover period, all subjects received 60 mg/kg body weight of functional Prolastin-C.
The pharmacokinetic parameters of Alpha1-PI in plasma, based on functional activity assays, showed comparability between Prolastin-C treatment and PROLASTIN treatment, as shown in Table 5.
| Treatment | AUC0-7 days (hr*mg/mL) Mean (%CV) | Cmax (mg/mL) Mean (%CV) | t1/2 (hr) Mean (%CV) |
|---|---|---|---|
| PROLASTIN®-C (n=22 or 23) | 155.9 (17%) | 1.797 (10%) | 146.3 (16%) |
| PROLASTIN® (n=22 or 23) | 152.4 (16%) | 1.848 (15%) | 139.3 (18%) |
The key pharmacokinetic parameter was the area under the plasma concentration-time curve (AUC0-7days) following 8 weeks of treatment with Prolastin-C or PROLASTIN. The 90% confidence interval (0.97-1.09) for the ratio of AUC0-7days for Prolastin-C and PROLASTIN indicated that the 2 products are pharmacokinetically equivalent. Figure 1 shows the concentration (functional activity) vs. time curves of Alpha1-PI after intravenous administration of Prolastin-C and PROLASTIN.
Figure 1: Mean Plasma Alpha1-PI Concentration (functional activity) vs. Time Curves Following Treatment with Prolastin-C or PROLASTIN
Trough levels measured during the PK study via an antigenic content assay showed Prolastin-C treatment resulted in a mean trough of 16.9 ± 2.3 µM and PROLASTIN resulted in a mean trough of 16.7 ± 2.7 µM. Using the functional activity assay, Prolastin-C resulted in a mean trough of 11.8 ± 2.2 µM and PROLASTIN resulted in a mean trough of 11.0 ± 2.2 µM.
A total of 62 unique subjects were studied in 2 clinical studies. In addition to the pharmacokinetic study described in [12.3], a multi-center, open-label single arm safety study was conducted to evaluate the safety and tolerability of Prolastin-C. In this study, 38 subjects were treated with weekly IV infusions of 60 mg/kg body weight of Prolastin-C for 20 weeks. Half the subjects were naïve to previous Alpha1-PI augmentation prior to study entry and the other half were receiving augmentation with PROLASTIN prior to entering the study. A diagnosis of severe AAT deficiency was confirmed by the demonstration of the PiZZ genotype in 32 of 38 (84.2%) subjects, and 6 of 38 (15.8%) subjects presented with other alleles known to result in severe AAT deficiency. These groups were distributed evenly between the naïve and non-naïve cohorts. Results from the study are discussed in [6.2]. The clinical efficacy of Prolastin-C or any Alpha1-PI product in influencing the course of pulmonary emphysema or pulmonary exacerbations has not been demonstrated in adequately powered, randomized, controlled clinical trials.
Prolastin-C is supplied in single-use vials with the total Alpha1-PI functional activity, in milligrams, stated on the label of each vial. Each product package contains a single vial of Prolastin-C, one 20 mL vial of Sterile Water for Injection, USP, a transfer needle, and a filter needle. Prolastin-C is supplied in the following size:
| NDC Number | Approximate Alpha1 -PI Functional Activity | Diluent |
|---|---|---|
| 13533-700-01 | 1000 mg | 20 mL |
Prolastin-C should be stored at temperatures not to exceed 25°C (77°F) for the period indicated by the expiration date on its label. Freezing should be avoided as breakage of the diluent bottle might occur.
Inform patients of the signs of hypersensitivity reactions including hives, generalized urticaria, tightness of the chest, dyspnea, wheezing, faintness, hypotension, and anaphylaxis. Patients should be advised to discontinue use of the product and contact their physician and/or seek immediate emergency care, depending on the severity of the reaction, if these symptoms occur.
Inform patients that Prolastin-C is made from human plasma and may contain infectious agents that can cause disease (e.g., viruses and, theoretically, the CJD agent). Inform patients of the risk that Prolastin-C may transmit an infectious agent, but that this risk has been reduced by screening plasma donors for prior exposure to certain viruses, by testing the donated plasma for certain virus infections and by inactivating and/or removing certain viruses during manufacturing. (See Warnings and Precautions [5.2]). Inform patients that administration of Prolastin-C has been demonstrated to raise the plasma level of Alpha1-PI, but that the effect of this augmentation on pulmonary exacerbations and on the rate of progression of emphysema has not been demonstrated in adequately powered, randomized, controlled clinical trials for any Alpha1-PI product.
Manufactured by:
Talecris Biotherapeutics, Inc.
Research Triangle Park, NC 27709 USA
U.S. License No. 1716
NDC 13533-700-01
Alpha1-Proteinase Inhibitor (Human)
PROLASTIN® C
Solvent detergent treated
Nanofiltered
Talecris Biotherapeutics
The patient and physician should discuss the risks and benefits of this product.
No preservative
For intravenous administration only
Sterile—nonpyrogenic
Reconstitute with 20 mL diluent sterile water for injection, USP.
Store at temperatures not to exceed 25°C (77°F). Do not freeze.
Dosage and administration:
Read package insert.
Rx only
Talecris Biotherapeutics, Inc.
Research Triangle Park, NC 27709 USA
U.S. License No. 1716
Alpha1-Proteinase Inhibitor (Human)
Prolastin® C
Sovent detergent treated
Nanofiltered
Dosage and administration:
Read enclosed package insert.
Store at temperatures not to exceed not to exceed 25(degrees)C (77(degrees)F.
Do not freeze.
Talecris Biotherapeutics
NDC 13533-700-01
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| Marketing Information | |||
| Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date |
| BLA | BLA103174 | 01/31/1987 | |
