![[U.S. Food and Drug Administration]](https://webarchive.library.unt.edu/eot2008/20081028100813im_/http://www.fda.gov/icon/header.gif){kind=icon}
(Posted: 7/7/98, Ismotic & Patanol added: 7/8/98, Hemabate, Crinone, Premarin added: 7/10/98,
Dolobid, Fioricet with Codiene and Indocin IV added: 7/14/98, Flomax added: 7/15/98)
Note: The following summaries include only those safety-related sections that have been modified, and therefore do not contain all the information needed for safe and effective prescribing. Contact the manufacturer for the complete labeling/package insert.
NB: Comparison made to 1998 Physicians' Desk Reference (PDR), if drug's labeling included in the PDR.
Compiled with the help of:
Elizabeth Felts, 1999 Pharm. D. Candidate
McWhorter School of Pharmacy
Samford University
Birmingham, AL
|
(timolol maleate) |
(buspirone HCl) |
(betaine anhydrous) |
||
(diflunisal) |
(acetaminophen/ butalbital/ caffeine/ codeine phosphate) |
(tamsulosin HCl) |
(alendronate Na) | |
(carboprost tromethamine) |
(propranolol HCl/ hydrochlorothiazide) |
(indomethacin/ Na trihydrate) |
(isosorbide) |
|
(mivacurium Cl) |
(mitoxantrone) |
(pimozide) |
||
(olopatadine HCl) |
(pravastatin Na) |
(conjugated estrogens) |
(conjugated estrogens) |
|
& PREMPHASE (conjugated estrogens/ medroxyprogesterone acetate) |
(salmeterol xinafoate) |
(salmeterol xinafoate) |
||
(timolol maleate/ hydrochlorothiazide) |
(nevirapine |
(lisinopril/ hydrochlorothiazide) |
||
(lisinopril) |
(cetirizine HCl) |
Quinidine (new subsection): "Potentiated systemic beta-blockade (e.g., decreased heart rate) has been reported during combined treatment with quinidine and timolol, possibly because quinidine inhibits the metabolism of timolol via the P-450 enzyme, CYP2D6.
" Clonidine (new subsection): "Beta adrenergic blocking agents may exacerbate the rebound hypertension which can follow the withdrawal of clonidine. If the two drugs are coadministered, the beta adrenergic blocking agent should be withdrawn several days before the gradual withdrawal of clonidine. If replacing clonidine by beta-blocker therapy, the introduction of beta adrenergic blocking agents should be delayed for several days after clonidine administration has stopped."
[Note: The following changes appear in the 1998 PDR.]
"Postmarketing experience has shown an adverse experience profile similar to that given above. Voluntary reports since introduction have included rare occurrences of allergic reactions (including uticaria), angioedema, cogwheel rigidity, dizziness (rarely reported as vertigo), dystonic reactions, ataxias, extrapyramidal symptoms, dyskinesias (acute and tardive), ecchymosis, emotional lability, serotonin syndrome, transient difficulty with recall, urinary retention, and visual changes (including tunnel vision). Because of the uncontrolled nature of these spontaneous reports, a causal relationship to BuSpar ["buspirone hydrochloride, USP" deleted] treatment has not been determined."
N.B. Throughout label, "Crinone 90 mg" replaced by "Crinone 8%"
Secondary Amenorrhea (new subsection): "In three parallel, open-label studies (COL1620-004US, COL1620-005US, COL1620-009US), 127 women (aged 18-44) with hypothalamic amenorrhea or premature ovarian failure were randomized to receive either CRINONE 4% (n=62) or Crinone 8% (n=65). All women were treated with either conjugated estrogens 0.625 mg daily (n=100) or transdermal estradiol (delivering 50 mcg/day) twice weekly (n=27).
"Estrogen therapy was continuous for the entire three 28-day cycle studies. At Day 15 of the second cycle (six weeks after initiating estrogen replacement), women who demonstrated adequate response to estrogen therapy (by ultrasound) and who continued to be amenorrheic received Crinone every other day for six doses (Day 15 through Day 25 of the cycle).
"In cycle 2, Crinone 4% induced bleeding in 79% of women and Crinone 8% induced bleeding in 77% of women. In the third cycle, estrogen was continued and Crinone was administered every other day beginning on day 15 for six doses. On Day 24 an endometrial biopsy was performed. In 53 women who received Crinone 4%, biopsy results were as follows: 7% proliferative, 40% late secretory, 19% mid secretory, 13% early secretory, 7% atrophic, 6% menstrual endometrium, 6% inactive endometrium and 2% negative endometrium. In 54 women who received Crinone 8%, biopsy results were as follows: 44% late secretory, 19% mid secretory, 11% early secretory, 19% atrophic, 5% menstrual endometrium and 2% 'oral contraceptive like' endometrium."
"Crinone 4% is indicated for the treatment of secondary amenorrhea.
"Crinone 8% is indicated for use in women who have failed to respond to treatment with Crinone 4%."
"In cases of breakthrough bleeding, as in all cases of irregular vaginal bleeding , nonfunctional causes should be considered. In cases of undiagnosed vaginal bleeding, adequate diagnostic measures should be undertaken."
Secondary Amenorrhea (new subsection):
"In three studies, 127 women with secondary amenorrhea received estrogen replacement
therapy and Crinone 4% or 8% every other day for six doses. Treatment emergent adverse
events during estrogen and Crinone treatment that occurred in 5% or more of women are
shown in Table 5."
Table 5 Estrogen + CRINONE 4% N=62 Estrogen+ CRINONE 8% N=65 Body as a Whole Abdominal Pain 3 (5%) 6 (9%) Appetite Increased 3 (5%) 5 (8%) Bloating 8 (13%) 8 (12%) Cramps NOS 12 (19%) 17 (26%) Fatigue 13 (21%) 14 (22%) Central and Peripheral Nervous System Headache 12 (19%) 10 (15%) Gastro-Intestinal System Nausea 5 (8%) 4 (6%) Musculo-Skeletal System Back Pain 5 (8%) 2 (3%) Myalgia 5 (8%) 0 (0%) Psychiatric Depression 12 (19%) 10 (15%) Emotional Lability 14 (23%) 14 (22%) Sleep Disorder 11 (18%) 12 (18%) Reproductive, Female Vaginal Discharge 7 (11%) 2 (3%) Resistance Mechanism Upper Respiratory Tract Infection 3 (5%) 5 (8%) Skin and Appendages Pruritis genital 1 (2%) 4 (6%)
"Additional adverse events reported in women at a frequency < 5% in the Crinone
ART and secondary amenorrhea studies and not listed in the tables above include:"
List
revised (new text in italics)
Autonomic Nervous System: mouth dry, sweating increased
Secondary Amenorrhea (new subsection): "Crinone 4% is administered vaginally
every other day up to a total of six doses. For women who fail to respond, a trial of
Crinone 8% every other day up to a total of six doses may be instituted.
"It is important to note that a dosage increase from the 4% gel can only be accomplished by using the 8% gel. Increasing the volume of gel administered does not increase the amount of progesterone absorbed."
Sentence added to end section -
"The Patient Information Sheet contains special instructions for using the applicator at
altitudes above 2500 feet in order to avoid a partial release of Crinone before vaginal
insertion."
Receiving Estrogen Treatment and CRINONE Every Other Day
Studies COL1620-004US, COL1620-005US, COL1620-009US
Body as a Whole: abnormal crying, allergic reaction, allergy,
appetite decreased, asthenia, edema, face edema, ["fatigue" deleted] fever,
hot flushes, influenza-like symptoms, water retention, xerophthalmia
Cardiovascular, General: syncope
Central and Peripheral Nervous System: migraine, tremor
Gastro-Intestinal: dyspepsia, eructation, flatulence, gastritis, toothache
Metabolic and Nutritional: thirst
Musculo-Skeletal System ["Disorders" deleted]: back pain, leg pain, skeletal pain
Neoplasm: benign cyst
Platelet, Bleeding & Clotting: purpura
Psychiatric: ["Disorders: emotional lability" deleted] aggressive reactions,
forgetfulness,
insomnia
Red Blood Cell: anemia
Reproductive, Female: dysmenorrhea, premenstrual tension, vaginal dryness
Resistance Mechanism ["Disorders" deleted]: infection, pharyngitis, sinusitis,
["upper respiratory tract infection," deleted] urinary tract infection
Respiratory System ["Disorders" deleted]: asthma, dyspnea, hyperventilation, rhinitis
Skin and Appendages ["Disorders" deleted]: acne, pruritis, rash, seborrhea,
skin discoloration, skin
disorder, urticaria
Urinary System ["Disorders" deleted]: cystitis, dysuria, micturition
frequency
Vision Disorders: conjunctivitis
"Mix with 4 to 6 ounces of water , juice, milk, or formula, until completely dissolved , or mix with food, then ["drink" deleted] ingest immediately."
"The prescribed amount of Cystadane should be measured with the measuring scoop provided (one level 1.7 cc scoop is equal to 1 gram of betaine anhydrous powder) and then dissolved in 4 to 6 ounces of water, juice, milk, or formula, or mix with food for immediate ingestion."
"Safety and effectiveness of Dolobid in ["infants and children" deleted] pediatric patients have not been established [", and" deleted]. Use of ["the drug" deleted] Dolobid in ["children" deleted] pediatric patients below the age of 12 years is not recommended.
Special Senses (new subsection): " Hearing loss"
"Safety and effectiveness in ["children below the age of 12" deleted] pediatric patients have not been established."
"Harderian gland (a retro-orbital gland not present in humans) adenomas were increased in high-dose female mice (p=0.003) in a 92-week carcinogenicity study at doses of alendronate of 1, 3, and 10 mg/kg/day (males) or 1, 2, and 5 mg/kg/day (females). These doses are equivalent to 0.5 to 4 times the 10 mg human dose based on surface area, mg/m2. The relevance of this finding to humans is unknown.
"Parafollicular cell (thyroid) adenomas were increased in high-dose male rats (p=0.003) in a 2-year carcinogenicity study at doses of 1 and 3.75 mg/kg body weight. These doses are equivalent to 1 and 3 times the 10 mg human dose based on surface area. The relevance of this finding to humans is unknown. "
"Safety and effectiveness in pediatric patients has not been established."
"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 subjects on propranolol."
General: Propranolol Hydrochloride (Inderal): Risk of anaphylactic reaction (new subsection): -
"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."
General: Hydrochlorothiazide: First sentence deleted -
"Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals."
Carcinogenesis, Mutagenesis, Impairment of Fertility: -
Existing text -
"Long-term studies in animals have been conducted to evaluate toxic effects and carcinogenic potential. In 18-month studies, in both rats and mice, employing doses up to 150 mg/kg/day there was no evidence of significant drug-induced toxicity. There were no drug-related tumorigenic effects at any of the dosage levels. Reproductive studies in animals did not show any impairment of fertility that was attributable to the drug."
deleted and replaced with -
"Combinations of propranolol and hydrochlorothiazide have not been evaluated for carcinogenic or mutagenic potential or for potential to adversely affect fertility.
"Propranolol Hydrochloride: 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).
"Hydrochlorothiazide: Two-year feeding studies in mice and rates conducted under the auspices of the National Toxicology Program (NTP) uncovered no evidence of a carcinogic 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.
"Hydroclorothiazide 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, or 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."
Pregnancy: Pregnancy Category C: New first paragraph -
"Combinations of propranolol and hydrochlorothiazide have not been evaluated for effects on pregnancy in animals. There are no adequate and well-controlled studies of propranolol, hydrochlorothiazide, or Inderide in pregnant women. Inderide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus."
Propranolol Hydrochloride (Inderal): Existing text deleted and replaced with -
"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 Inderide), 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 was also administered (in the feed) to rabbits (throughout pregnancy and lactation) as doses as high as 150 mg/kg/day (> 45 times the dose of propranolol contained in the maximum recommended daily human dose of Inderide). No evidence of embryo or neonatal toxicity was noted. Teratogenicity was not noted in either species. Intrauterine growth retardation has been reported in neonates whose mothers received propranolol at parturition have exhibited bradycardia, hypoglycemia and respiratory depression. Adequate facilities for monitoring these infants at birth should be available."
Hydrochlorothiazide: Subsection revised (new text in italics) -
"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 [" pregnancy" deleted] 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 which have occurred in the adult.
"["Available information indicates that hydrochlorothiazide at doses as high as 1320 times the MRHD was not teratogenic in pregnant rats." deleted]"
Nursing Mothers: Existing separate subsections for "Propranolol Hydrochloride (Inderal)" and "Hydrochlorothiazide" combined into one subsection with the following text -
"Propranolol and thiazides are excreted in human milk. Caution should be exercised when Inderide LA is administered to a nursing woman."
Pediatric Use: Existing separate subsections for "Propranolol Hydrochloride (Inderal)" and "Hydrochlorothiazide" combined into one subsection with the following text -
"Safety and effectiveness in pediatric patients have not been established."
"Hydrochlorothiazide can be given at doses of ["25 to 100 mg" deleted] 12.5 to 50 mg per day when used alone [", but in most patients, 50 mg exerts a maximal effect" deleted]."
"Studies in healthy young animals and in premature infants with patent ductus arteriosis indicated that, after the first dose of intravenous indomethacin, there was a transient reduction in cerebral blood flow velocity and cerebral blood flow. Similar decreases in mesenteric blood flow and velocity have been observed. The clinical significance of ["this effect has" deleted] these effects have not been established".
"Once reconstituted, the indomethacin solution may be injected intravenously ["over 5-10 seconds" deleted]."
Text added as new last sentence after above sentence -
"While the optimal rate of injection has not been established, published literature suggests an infusion rate over 20-30 minutes."
"Use where less risk of nausea and vomiting than that posed by other oral hyperosmotic agents as needed."
"No studies have been conducted in animals or in humans to evaluate the potential of these effects."
["Usage in" deleted] Pregnancy: Pregnancy Category B: Existing text deleted and replaced with –
Reproduction (fertility and teratology) studies have been performed in rats at doses approximately 5 times the recommended initial human dose of 1.5 gm/kg body weight and have revealed no evidence of impaired fertility or harm to the fetus due to isosorbide. Teratology studies have been performed with rabbits and rats given daily oral doses of isosorbide at 6.5 and 10 times, respectively, the recommended initial human dose during organogenesis without evidence of harm to the fetus. There are, however, no adequate and well-controlled studies in pregnant women. Because animal studies are not always predictive of human responses, this drug should be used during pregnancy only if clearly needed."
Pediatric Use (name changed from "Usage in Children"): Subsection revised (new text in italics) -
"Safety and effectiveness in ["children" deleted] pediatric patients have not been established."
"It is found in low concentration in plasma and extracellular fluids (3.5 to 5.0 mEq/liter in a healthy adult and child over 10 days old, 3.5 to 6.0 mEq/liter in a child less than 10 days old."
Text and table added at end of eighth paragraph -
"Average normal pediatric daily requirements are based on the child's weight as described in the table below:
|
Weight |
Fluid Requirements |
|
Up to 10 kg |
100 mL/kg |
|
11 to 20 kg |
1,000 mL + 50 mL/kg for |
|
Above 20 kg |
1,500 mL + 20mL/kg for each |
Pediatric Use (new subsection): -
"The safety and effectiveness of Normosol-R have been established in the age groups of birth to 16 years. Use of Normosol-R is supported by evidence from adequate and well-controlled studies in adults with additional data from post-marketing experience in the pediatric population."
"
"Novantrone is not indicated for intra-arterial injection. There have been reports of local/regional neuropathy, some irreversible, following intrathecal injection.
"Novantrone should not be given by intrathecal injection. There have been reports of neuropathy including paralysis and bowel and bladder dysfunction following intrathecal injection."
"Similarly, protease inhibitor drugs are also inhibitors of CYP 3A, and thus ORAP is contraindicated in patients receiving protease inhibitors such as ritonavir, saquinovir, indinavir, and nelfinavir."
"Patanol is contraindicated in persons with a known hypersensitivity to olopatadine hydrochloride or any component of ["this product" deleted] Patanol"
"Patanol is for topical use only and not for injection or oral use. ["Patients should be instructed not to instill Patanol (olopatadine hydrochloride ophthalmic solution) 0.1% while wearing contact lenses." deleted, moved to PRECAUTIONS and revised.]"
"Patients should be instructed not to ["instill Patanol (olopatadine hydrochloride ophthalmic solution) 0.1% while wearing contact lenses" deleted] wear a contact lens if their eye is red. Patanol should not be used to treat contact lens related irritation. The preservative in Patanol, benzalkonium chloride, may be absorbed by soft contact lenses. Patients who wear soft contact lenses and whose eyes are not red, should be instructed to wait at least ten minutes after instilling Patanol before they insert their contact lenses."
N.B. Ocular and nonocular experiences were combined.
"Headaches were reported at an incidence of 7%. The following ["additional ocular and nonocular" deleted] adverse ["reactions" deleted] experiences were reported ["at an incidence of" deleted] in less than 5% of patients: Asthenia, burning or stinging, cold syndrome, dry eye, foreign body sensation, hyperemia, keratitis, lid edema, pharyngitis, pruritus, rhinitis, sinusitis and taste perversion. Some of these events were similar to the underlying disease being studied."
"In one single dose study, pravastatin levels were found to be increased in cardiac transplant patients receiving cyclosporine."
"In vitro and in vivo data indicate that pravastatin is not metabolized by cytochrome P450 3A4 to a clinically significant extent. This has been shown in studies with known cytochrome P450 3A4 inhibitors (see diltiazem and itraconazole below). Other examples of cytochrome P450 3A4 inhibitors include ketoconazole, mibefradil, and erythromycin.
"Diltiazem - Steady-state levels of diltiazem (a known weak inhibitor of P450 3A4) had no effect on the pharmacokinetics of pravastatin. In this study, the AUC and Cmax of another HMG-CoA reductase inhibitor which is known to be metabolized by cytochrome P450 3A4 increased by factors of 3.6 and 4.3, respectively.
"Itraconazole - The mean AUC and Cmax for pravastatin were increased by factors of 1.7 and 2.5, respectfully, when given with Itraconazole (a potent P450 3A4 inhibitor which also inhibits p-glycoprotein transport) as compared to placebo. The mean t1/2 was not affected by itraconazole, suggesting that the relatively small increases in Cmax and AUC were due solely to increased bioavailability rather than a decrease in clearance, consistent with inhibition of p-glycoprotein transport by itraconazole. This drug transport system is thought to affect bioavailability and excretion of HMG-CoA reductase inhibitors, including pravastatin. The AUC and Cmax of another HMG-CoA reductase inhibitor which is known to be metabolized by cytochrome P450 3A4 increased by factors of 19 and 17, respectively, when given with itraconazole."
Warfarin: Existing text deleted and replaced with -
"Pravastatin had no clinically significant effect on prothrombin time when administered in a study to normal elderly subjects who were stabilized on warfarin."
Other Drugs: Subsection deleted
"6. Women on estrogen replacement therapy have not been reported to have an increased risk of thrombophlebitis and/or thromboembolic disease."
"In some epidemiological studies, women on estrogen replacement therapy, given alone or in combination with a progestin, have been reported to have an increased risk of thrombophlebitis, and/or thromboembolic disease, although the evidence is conflicting. Large dose of estrogen (5 mg conjugated estrogens per day), comparable to those used to treat cancer of the prostate and breast, have been shown in a large prospective clinical trial in men to increase the risk of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis. ["It cannot necessarily be extrapolated from men to women. However, to avoid the theoretical cardiovascular risk caused by high estrogen doses, the doses for estrogen replacement therapy should not exceed the recommended dose." deleted]
"The physician should be aware of the possibility of thrombotic disorders (thrombophlebitis, retinal thrombosis, cerebral embolism, and pulmonary embolism) during estrogen replacement therapy and be alert to their earliest manifestations. Should any of these occur or be suspected, estrogen replacement therapy should be discontinued immediately. Patients who have risk factors for thrombotic disorders should be kept under careful observation."
"Venous thromboembolism; pulmonary embolism."
"The following events have also been identified during postapproval use of Serevent in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to Serevent.
"["Postmarketing events includes" deleted"] Respiratory: Rare reports of upper airway symptoms of laryngeal spasm, irritation, or swelling such as stridor ["and" deleted] or choking.
"Cardiovascular: Hypertension, ["and" deleted] arrhythmias ["have been reported" deleted] (including atrial fibrillation, supraventricular tachycardia, extrasystoles)."
"In humans, ["salmeterol administered via inhalation aerosol inhibits both the early- and late-phase reponses to inhaled allergens, the latter persisting for over 30 hours after single dose when the bronchodilator effect is no longer evident." deleted] single doses of salmeterol administered via inhalation aerosol ["also" deleted] attenuate allergen-induced bronchial hyper-responsiveness."
Pharmacokinetics: Subsection revised (new text in italics) -
"Salmeterol acts locally in the lung; plasma levels therefore do not predict therapeutic effect. Because of the low therapeutic dose, systemic levels of salmeterol powder are low or undectable after inhalation of ["the" deleted] recommended dose["s" deleted] (50 mcg twice daily). Following chronic administration of an inhaled dose of 50 mcg of salmeterol powder twice daily, salmeterol was detected in plasma within 5 to 45 minutes in seven asthmatic patients; plasma concentrations were very low, with ["plasma" deleted] peak concentrations of 167 pg/mL ["105 to 309 pg/mL (mean concentration of 167 +/- 75 pg/mL)" deleted] and no accumulation with repeated doses. Oral administration of 1 mg of radiolabeled salmeterol (as salmeterol xinafoate) to two healthy subjects gave peak plasma salmeterol concentrations of about 650 pg/mL at about 45 minutes; the terminal elimination half-life was about 5.5 hours (one volunteer only)."
Pharmacodynamics: First two paragraphs revised (new text in italics) -
"Inhaled salmeterol, like other beta-adrenergic agonist drugs, can in some patients produce cardiovascular effects (see PRECAUTIONS). The cardiovascular effects (heart rate, blood pressure) associated with salmeterol inhalation aerosol ["administration have been shown to" deleted] occur with similar frequency, and are of similar type and severity, as those noted following albuterol ["inhalation aerosol" deleted] administration.
"The effects of rising doses of salmeterol and standard inhaled doses of albuterol were studied in volunteers and in patients with asthma. Salmeterol doses ["of" deleted] up to 84 mcg administered as inhalation aerosol resulted in heart rate increases of 3 to 16 beats/min, about the same as albuterol ["administered" deleted] dosed at 180 mcg by inhalation aerosol (4 - 10 beats/min). Patients receiving 50-mcg doses of salmeterol powder (n=60) underwent continuous electrocardiographic monitoring during two 12-hour periods after the first dose and after 1 month of therapy, and no clinically significant dysrhythmias were noted."
"Serevent Diskus is contraindicated in patients with a history of hypersensitivity to salmeterol or any of the components."
"When beginning treatment with Serevent Diskus, patients who have been taking inhaled, short-acting beta2-agonists on a regular basis (e.g., four times ["daily" deleted] a day) should be instructed to discontinue the regular use of these drugs and use them only for symptomatic relief ["if they develop" deleted] of acute asthma symptoms ["while taking Serevent Diskus" deleted] (See PRECAUTIONS: Information for Patients)."
Bullet #6 - Revised (new text in italics) -
"Pardoxical Bronchospasm: Inhalation of salmeterol xinafoate can produce paradoxical bronchospasm, ["that" deleted] which may be life threatening. If paradoxical bronchospasm occurs, Serevent Diskus should be discontinued immediately and alternative therapy instituted. It should be recognized that paradoxical bronchospasm, when associated with inhaled formulations, frequently occurs with the first use of a new canister or vial."
"Metabolic Effects: Doses of the related beta2-adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis. No effects on glucose have been seen with Serevent Diskus at recommended doses. ["Administration of beta2-adrenoceptor agonists may cause a decrease in serum potassium" deleted] Beta-adrenergic agonist medications may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to ["increase the likelihood of arrhythmias" deleted] produce adverse cardiovascular effects. The decrease is usually transient, not requiring supplementation."
Information for Patients: Bullet #5 revised (new text in italics) -
"Patients should be cautioned regarding ["potential" deleted] common adverse cardiovascular effects, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness [", related to the use of additional beta2-agonist" deleted]."
Drug Interactions: Short-Acting Beta-Agonists: Subsection revised (new text in italics) -
"In the two 12-week, repetitive-dose clinical trials (n=149), the mean daily need for additional beta2-agonist use ["in patients using salmeterol powder" deleted] was approximately 1 1/2 inhalations per day, but some patients used more. Twenty-six percent of ["the" deleted] patients ["in these trials" deleted] used ["between" deleted] at least 8 ["and 24" deleted] inhalations ["of short-acting beta-agonist" deleted] per day at least on one ["or more" deleted] occasion["s" deleted]. ["Nine percent of the patients in these trials averaged over 4 inhalations per day over the course of the 12-week trials." deleted] Fifteen percent used 9 to 24 inhalations at least once. There were 16 patients (11%) who averaged over 4 inhalations per day. Three of these used an average of 8 to 11 inhalations per day. In these 16 patients there was no observed increase in frequency of cardiovascular adverse events. ["was noted among the 3 patients who used an average of 8 to 11 inhalations per day; however," deleted] The safety of concomitant use of more than 8 inhalations per day of short-acting beta2-agonist with salmeterol powder has not been established. In 29 patients who experienced worsening of asthma while receiving salmeterol powder ["during these trials" deleted], albuterol ["therapy administered" deleted] via either nebulizer or inhalation aerosol (one dose in most ["cases" deleted] led to improvement in FEV1 and no increase in occurrence of cardiovascular adverse events."
Drug Interactions: Methylxanthines: Two paragraphs added at end of subsection -
"Beta-adrenergic receptor blocking agents not only block the pulmonary effect of beta-agonists, such as Serevent Diskus, but may produce severe bronchospasm in asthmatic patinets. Therefore, patients with asthma should not normally be treated with beta-blockers. However, under certain circumstances, e.g., as prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents in patients with asthma, In this setting, cardioselective beta-blockers could be considered, although they should be administered with caution.
"The ECG changes and/or hypokalemia that may result from the administration of nonpotassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of beta-agonists with nonpotassium-sparing diuretics."
Carcinogenesis, Mutagenesis, Impairment of Fertility: First paragraph revised (new text in italics) -
"In an 18-month oral carcinogenicity study in CD-mice, salmeterol xinafoate at oral doses of 1.4 mg/kg and above (approximately nine times the maximum recommended daily inhalation dose in adults based on comparison of the area-under-the plasma-concentration versus time curves [AUCs]) caused ["a" deleted] dose-related increases in the incidence of smooth muscle hyperplasia, cystic glandular hyperplasia, ["and" deleted] leiomyomas ["in" deleted] of the uterus, and cysts in the ovaries. The ["observed" deleted] incidence of leiomyosarcomas was not statistically significant. ["Tumors were observed at oral doses of 1.4 mg/kg per day and above (approximately 9 times the maximum recommended human daily inhalation dose in adults based on comparison of the areas under the plasma concentration vs. time curve [AUCs])." deleted] No tumors were seen at 0.2 mg/kg, ["per day (approximately" deleted] comparable to the maximum recommended human daily inhaltion dose in adults based on comparison of the AUCs)."
Use in Labor and Delivery: Subsection revised (new text in italics) -
"There are no well-controlled human studies that have investigated effects of salmeterol on preterm labor or labor at term. Because of the potential for beta-agonist interference with uterine contractility, use of Serevent Diskus for prevention of bronchospasm during labor should be restricted to those patients in whom the benefits clearly outweigh the risks."
Nursing Mothers: Subsection revised (new text in italics) -
"Plasma levels of salmeterol after inhaled therapeutic doses ["of salmeterol powder" deleted] are very low ["(105 to 300 pg/mL) in humans" deleted]. In ["lactating" deleted] rats [", dosed with radiolabeled salmeterol, levels of radioactivity were similar in plasma and milk. The xinafoate moiety is also transferred to milk in rats at concentrations of about half the corresponding level in plasma" deleted] salmeterol xinafoate is excreted in milk. However, since there is no experience with use of Serevent Diskus by nursing mothers, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Caution should be exercised when salmeterol xinafoate is administered to a nursing woman."
Geriatric Use: Second sentence revised (new text in italics) -
"No apparent differences in the efficacy and safety of Serevent powder were observed when geriatric patients were compared with younger patients in clnical trials."
Third sentence - the word "elderly" is replaced by the word "geriatric".
Observed During Clinical Practice (formerly named "Postmarketing Experience"): Subsection revised (new text in italics) -
"In extensive US and worldwide postmarketing experience ["with Serevent" deleted] , serious exacerbations of asthma, including some that have been fatal, have been reported. In most cases, these have occurred in patients with severe asthma and/or in some patients in whom asthma has been acutely deteriorating (see WARNINGS no.1), but they have also occurred in a few patients with less severe asthma as well. It was not possible from these reports to determine whether Serevent contributed to these events or simply failed to relieve the deteriorating asthma.
"The following events have also been identified during postapproval use of Serevent in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to Serevent.
"["Postmarketing experience includes" deleted] Respiratory: Rare reports of upper airway symptoms of laryngeal spasm, irritation, or swelling such as stridor or choking.
"Cardiovascular: Hypertension, ["and" deleted] arrhythmias (including atrial fibrillation supraventricular tachycardia, extrasystoles) ["have been reported" deleted]."
"signs and symptoms" revised to "symptoms"
Third paragraph, second sentence revised -
"The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind ["the possibility" deleted] that such medication can produce bronchospasm."
Third paragraph, last sentence deleted -
"Cardiac monitoring is recommended in cases of overdosage."
"In studies where geriatric patients (65 years of age or older, see PRECAUTIONS) have been treated with Serevent powder, efficacy and safety of 50 mcg given twice daily (morning and evening) did not differ from that in younger patients. Consequently, no dosage adjustment ["with Serevent Diskus" deleted] is recommended."
"Potentiated systemic beta-blockade (e.g., decreased heart rate) has been reported during combined treatment with quinidine and timolol, possibly because quinidine inhibits the metabolism of timolol via the P-450 enzyme, CYP2D6.
"Beta adrenergic blocking agents may exacerbate the rebound hypertension which can follow the withdrawal of clonidine. If the two drugs are coadministered, the beta adrenergic blocking agent should be withdrawn several days before the gradual withdrawal of clonidine. If replacing clonidine by beta-blocker therapy, the introduction of beta adrenergic blocking agents should be delayed for several days after clonidine administration has stopped."
In addition, the following specific changes were made -
"["Viramune (nevirapine) is indicated for use in combination with nucleoside analogues for the treatment of HIV-1 infected adults who have experienced clinical and/or immunologic deterioration. This indication is based on analysis of changes in surrogate endpoints in studies of up to 48 weeks duration. At present, there are no results from controlled clinical trials evaluating the effect of Viramune with nucleoside analogues on the clinical progression of HIV-1 infection, such as the incidence of opportunistic infections or survival." deleted]"
"["The duration of benefit from antiretroviral therapy may be limited. Alteration of antiretroviral therapies should be considered if disease progression occurs while patients are receiving Viramune." deleted]"
Severe and life-threatening skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis), including fatal cases, have occurred in patients treated with Viramune. (See WARNINGS).
"Severe and life-threatening hepatoxicity, including fatal hepatic necrosis, has occurred in patients treated with Viramune. (see WARNINGS).
"Resistant virus emerges rapidly and uniformly when Viramune is administered as monotherapy. Therefore, Viramune should always be administered in combination with ["at least one additional" deleted] antiretroviral agents.
"["Viramune has been associated with severe rash, which in some cases have been life-threatening. When severe rash occurs, Viramune must be discontinued." deleted]"
"In cell culture, nevirapine demonstrated additive to synergistic activity against HIV in drug combination regimens with zidovudine (ZDV), didanosine (ddI), stavudine (d4T), lamivudine (3TC), ["and" deleted] saquinavir and indinavir."
"Nucleoside Analogues: No dosage adjustments are required when Viramune is taken in combination with ZDV, ddI, or ddC. ["When the ZDV data were pooled from two studies (n=33) in which HIV-1-infected patients received Viramune 400mg/day either alone or in combination with 200-300 mg/day ddI or 0.375 to 0.75 mg/day ddC on a background of ZDV therapy, nevirapine produced a non-significant decline of 13% in ZDV AUC and a non-significant increase of 5.8% in ZDV Cmax. In a subset of patients (n=6) who were administered nevirapine 400 mg/day and ddI on a background of ZDV therapy, nevirapine produced a significant decline of 32% in ZDV AUC and a non-significant decline of 27% in ZDV Cmax. Paired data suggest that ZDV had no effect on the pharmacokinetics of nevirapine. In one crossover study, nevirapine had no effect on the steady-state pharmacokinetics of either ddI (n=18) or ddC (n=6)."deleted]"
"["Available data on the potential interactions between nevirapine and other CYP3A substrates are limited and preliminary; therefore, recommendations for dose adjustments cannot be made. (see PRECAUTIONS, Drug Interactions, for recommendations regarding rifampin, rifabutin, protease inhibitors and oral contraceptives)." deleted]"
"Results from studies in HIV-1 infected patients who were adminsitered Viramune with different combinations of ddI or ddC, on a background of ZDV therapy, indicated that no clinically significant pharmacokinetic interactions occurred when the nucleoside analogues were administered in combination with Viramune.
"Protease Inhibitors: In the following three studies, Viramune was given 200 mg once daily for two weeks followed by 200 mg twice daily for 28 days:
"Ritonavir: No dosage adjustments are required when Viramune is taken in combination with ritonavir. Results from a 49-day study in HIV-infected patients (n=14) administered Viramune and ritonavir (600 mg b.i.d. [using a gradual dose escalation regimen]) indicated that their coadministration did not affect ritonavir AUC or Cmax. Comparison of nevirapine pharmacokinetics from this study to historical data suggested that coadministration did not affect the pharmacokinetics of nevirapine.
"Indinavir: Results from a 36-day study in HIV-infected patients (n=19) administered Viramune and indinavir (800mg q 8 h) indicated that their coadministration led to a 28% mean decrease (95% CI -39, -16) in indinavir AUC and 11 % mean decrease (95% CI -49, +59) in indinavir Cmax. The clinical significance of this interaction is not known. Comparison of nevirapine pharmacokinetics from this study to historical data suggested that coadministration did not affect the pharmacokinetics of nevirapine.
"Saquinavir: Results from a 42-day study in HIV-infected patients (n=23) administered Viramune and saquinavir (hard gelatin capsules, 600 mg t.i.d.) indicated that their coadministration led to a 24% mean decrease (95% CI-42, -1) in saqinavir AUC and 28 % mean decrease (95% CI -47, -1) in saqinavir Cmax. The clinical significance of this interaction is not known. Coadministration did not affect the pharmacokinetics of nevirapine.
"In vitro: Studies using human liver microsomes indicated that the formation of nevirapine hydroxylated metabolites was not affected by the presence of dapsone, rifabutin, rifampin, and trimethoprim/sulfamethoxazole. Ketoconazole significantly inhibited the formation of nevirapine hydroxylated metabolites.
"In vivo: ketoconazole: Viramune and ketoconazole should not be administered concomitantly. Ketoconazole AUC and Cmax decreased by a median 63% (95% CI -95, +33) and 40% (95% CI -52, +11), respectively, in HIV-infected patients (n=22) who were given Viramune 200 mg once daily for two weeks followed by 200 mg twice daily for two weeks along with ketoconazole 400 mg daily. (See PRECAUTIONS, Drug Interactions.) Comparison of the pharmacokinetics from this study to historical data suggested that coadministration with ketoconazole may result in a 15-30% increase in nevirapine plasma concentrations. The clinical significance of this observation is not known.
"Monitoring of nevirapine ["steady-state nevirapine trough" deleted] plasma concentrations in patients who received long-term Viramune treatment ["in combination with ketoconazole (n=11) revealed no evidence of a significant effect on nevirapine metabolism." deleted] indicate that steady-state nevirapine trough plasma concentrations were elevated in patients who received cimetidine (+21%, n=11) and macrolides (+12%, n=24), known inhibitors of CYP3A.
"Steady-state nevirapine trough concentrations were reduced in patients who received rifabutin (-16%, n=19) and rifampin (-37%, n=3), known inducers of CYP3A. Nevirapine is an inducer of CYP3A, with maximal induction occurring within 2-4 weeks of initiating multiple-dose therapy. Other compounds that are substrates of CYP3A may have decreased plasma concentrations when co-administered with Viramune. Therefore, careful monitoring of the therapeutic effectiveness of CYP3A-metabolized drugs is recommended when taken in combination with Viramune. (See PRECAUTIONS, Drug Interactions, for recommendations regarding rifampin, rifabutin, and oral contraceptives)"
"Viramune (nevirapine) ["in combination with nucleoside analogues is indicated for the treatment of HIV-1 infected adults who have experienced clinical and/or immunologic deterioration." deleted] is indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection. This indication is based on analysis of changes in surrogate endpoints ["in studies of up to 48 weeks duration" deleted]. At present, there are no results from controlled clinical trials evaluating the effect of Viramune ["with nucleoside analogues" deleted] in combination with other antiretroviral agents on the clinical progression of HIV-1 infection, such as the incidence of opportunistic infections or survival. ["The duration of benefit from antiretroviral therapy may be limited. Alteration of antiretroviral therapy should be considered if disease progression occurs while patients are receiving Viramune." deleted]"
"Severe and life-threatening skin reactions have occurred in patients with Viramune, including Stevens-Johnson syndrome ["(SJS)" deleted] and toxic epidermal necrolysis. Fatal cases of toxic epidermal necrolysis have been reported. Viramune must be discontinued in patients developing a severe rash or a rash accompanied by constitutional symptoms such as fever, blistering, oral lesions, conjunctivitis, swelling, muscle or joint aches, or general malaise. (see PRECAUTIONS, Information for Patients; ADVERSE REACTIONS) Viramune therapy must be initiated with a 14 day lead in period of 200 mg/day, which has been shown to reduce the frequency of rash. If rash is observed during this lead in period, dose escalation should not occur until the rash has resolved. (see DOSAGE AND ADMINISTRATION).
"Severe or life-threatening hepatotoxicity, including fatal fulminant hepatitis (transaminase elevations, with or without hyperbilirubinemia, prolonged partial thromboplastin time, or eosinophilia), has occurred in patients treated with Viramune. Some of these cases began in the first few weeks of therapy and some were accompanied by rash. Viramune administration should be interrupted in patients experiencing moderate or severe ALT or AST abnormalities until these return to baseline values. Viramune should be permanently discontinued if liver function abnormalities recur upon readministration. Monitoring of ALT and AST is strongly recommended, especially during the first six months of Viramune treatment. (See PRECAUTIONS, Information for Patients; ADVERSE REACTIONS; DOSAGE AND ADMINISTRATION)"
"["Viramune therapy must be initiated with a 14 day lead in period of 200 mg/day, which has been shown to reduce the frequency of rash. Dose escalation should not occur if rash is observed during this lead in period until the rash has resolved. (see DOSAGE AND ADMINISTRATION)." deleted]"
"["When administering Viramune as part of an antiretroviral treatment regimen, the complete product information for each therapeutic component should be consulted before initiation of treatment. While" deleted] Nevirapine is extensively metabolized by the liver and nevirapine metabolites are extensively eliminated by the kidney. ["the" deleted] However, the pharmacokinetics of nevirapine have not been evaluated in patients with either hepatic or renal dysfunction. Therefore, Viramune should be used with caution in these patient populations.
"The duration of clinical benefit from antiretroviral therapy may be limited. Patients receiving Viramune or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection, and therefore should remain under close clinical observation by physicians experienced in the treatment of patients with associated HIV diseases.
"When administering Viramune as part of an antiretroviral regimen, the complete product information for each therapeutic component should be consulted before initiation of treatment. ["Abnormal liver function tests have been reported with Viramune, some in the first few weeks of therapy, including cases of hepatitis. Viramune administration should be interrupted in patients experiencing moderate or severe liver function test abnormalities until liver function tests return to baseline values. Viramune treatment should be permanently discontinued if liver function abnormalities recur on readministration." deleted]"
Drug Interactions: First sentence revised (new text in italics) -
"["Although clinical studies have not been conducted," deleted] The induction of CYP3A by nevirapine may result in lower plasma concentrations of other concomitantly administered drugs that are extensively metabolized by CYP3A."
Protease Inhibitors: subsection deleted.
Ketoconazole (new subsection): "Viramune and ketoconazole should not be administered concomitantly. Coadministration of nevirapine and ketoconazole resulted in a significant reduction in ketoconazole plasma concentrations. (See CLINICAL PHARMACOLOGY, Drug Interactions)."
Information for Patients: Subsection reorganized and revised (new text in italics) -
"Patients should be instructed that the major toxicity of Viramune is rash and should be advised to promptly notify their physician of any rash. The majority of rashes associated with Viramune occur within the first 6 weeks of initiation of therapy. ["Therefore, patients should be monitored carefully for the appearance of rash during this period." deleted] Patients should be instructed that, if any rash occurs during the two-week lead-in ["dosing" deleted] period, the Viramune dose should not be escalated until the rash resolves. Any patient experiencing severe rash or a rash accompanied by constitutional symptoms such as fever, blistering, oral lesions, conjunctivitis, swelling, muscle or joint aches, or general malaise should discontinue medication and consult a physician.
"Patients should be instructed that abnormal liver function tests and cases of clinical hepatitis, including fatal fulminant hepatitis, have been reported with Viramune. Liver function tests should be monitored, especially during the first six months of therapy. Viramune administration should be interrupted in patients experiencing moderate or severe liver function test abnormalities, until liver function tests return to baseline values; Viramune should be permanently discontinued if liver function abnormalities recur upon readministration. Patients should be instructed to consult their physicians immediately should symptoms of hepatitis occur.
"["Patients should be instructed that" deleted] Oral contraceptives and other hormonal methods of birth control should not be used as a method of contraception in women taking Viramune. (See PRECAUTIONS, Drug Interactions).
"Patients should be informed that Viramune therapy has not been shown to reduce the risk of transmission of HIV-1 to others through sexual contact or blood contamination. The long-term effects of Viramune are unknown at this time.
"["Patients should be informed that" deleted] Viramune is not a cure for HIV-1 infection; ["and that they" deleted] patients may continue to experience illnesses associated with advanced HIV-1 infection, including opportunistic infections. Treatment with Viramune has not been shown to reduce the incidence or frequency of such illnesses; ["and" deleted] patients should be advised to remain under the care of a physician when using Viraume.
"Patients should be informed to take Viramune every day as prescribed. Patients should not alter the dose without consulting their doctor. If a dose is missed, patients should take the next dose as soon as possible. However, if a dose is skipped, the patient should not double the next dose. Patients should be advised to report to their doctor the use of any other medications.
"["Viramune may interact with some drugs; therefore, patients should be advised to report to their doctor the use of any other medications." deleted]"
"Asymptomatic elevations of GGT levels are more frequent in Viramune recipients than in controls. Because clinical hepatitis has ["occasionally" deleted] been reported in Viramune-treated patients, monitoring of ["liver function tests should be considered" deleted] ALT (SGPT) and AST (SGOT) is strongly recommended, especially during the first six months of Viramune treatment (See WARNINGS)."
"There is no known antidote for Viramune overdosage. ["No acute toxicities or sequelae were reported for one patient who ingested 800 mg of Viramune for one day." deleted] Cases of Viramune overdose at doses ranging from 800 to 1800 mg per day for up to 15 days have been reported. Patients have experienced events including edema, erythema nodosum, fatigue, fever, headache, insomnia, nausea, pulmonary infiltrates, rash, vertigo, vomiting and weight decrease. All events subsided following discontinuation of Viramune."
"The recommended dose for Viramune is one 200 mg tablet daily for the first 14 days (this lead-in period should be used because it has been found to lessen the frequency of rash), followed by one 200 mg tablet twice daily, in combination with ["nucleoside analogue" deleted] antiretroviral agents. For concomitantly administered ["nucleoside" deleted] antiretroviral therapy, the manufacturer's recommended dosage and monitoring should be followed."
Monitoring of Patients: "(See WARNINGS)" added at end of subsection.
Dosage Adjustment: Last paragraph revised (new text in italics) -
"Viramune administration should be interrupted in patients experiencing moderate or severe liver function test abnormalities (excluding GGT), until the liver function test elevations have returned to baseline. Viramune may then be restarted at ["half the previous dose level" deleted] 200 mg per day. Increasing the daily dose to 200 mg twice daily should be done with caution, after extended observation. Viramune should be permanently discontinued if moderate or severe liver function test abnormalities recur. (See ["PRECAUTIONS" deleted] WARNINGS)"
"Lisinopril monotherapy is an effective treatment of hypertension in once daily doses of 10 - 80 mg, while hydrochlorothiazide monotherapy is effective in doses of ["25 - 100 mg" deleted] 12.5 - 50 mg per day."
Respiratory: "eosinophilic pneumonitis" added.
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