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DRUGS & SUPPLEMENTS
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Slow-Theo SR
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Slow-Theo SR uses
- Indications and usage
- Contraindications
- Warnings
- Precautions
- Adverse reactions
- Overdosage
- Dosage and administration
- How supplied
INDICATIONS AND USAGE
Slow-Theo SR Extended-release capsules are indicated for the treatment of the symptoms and reversible airflow obstruction associated with chronic asthma and other chronic lung diseases, e.g., emphysema and chronic bronchitis.
CONTRAINDICATIONS
Slow-Theo SR Extended - release capsules is contraindicated in patients with a history of hypersensitivity to Slow-Theo SR or other components in the product.
WARNINGS
Concurrent Illness:
Slow-Theo SR should be used with extreme caution in patients with the following clinical conditions due to the increased risk of exacerbation of the concurrent condition:
- Active peptic ulcer disease
- Seizure disorders
- Cardiac arrhythmias
Conditions That Reduce Slow-Theo SR Clearance:
There are several readily identifiable causes of reduced Slow-Theo SR clearance. If the total daily dose is not appropriately reduced in the presence of these risk factors, severe and potentially fatal Slow-Theo SR toxicity can occur. Careful consideration must be given to the benefits and risks of Slow-Theo SR use and the need for more intensive monitoring of serum Slow-Theo SR concentrations in patients with the following risk factors:
Age
- Neonates
- Children <1 year
- Elderly (>60 years)
Concurrent Diseases
- Acute pulmonary edema
- Congestive heart failure
- Cor-pulmonale
- Fever; ≥102° for 24 hours or more; or lesser temperature elevations for longer periods
- Hypothyroidism
- Liver disease; cirrhosis, acute hepatitis
- Reduced renal function in infants <3 months of age
- Sepsis with multi-organ failure
- Shock
Cessation of Smoking
Drug Interactions Adding a drug that inhibits Slow-Theo SR metabolism or stopping a concurrently administered drug that enhances Slow-Theo SR metabolism (e.g., carbamazepine, rifampin)..
When Signs or Symptoms of Slow-Theo SR Toxicity Are Present:
Whenever a patient receiving Slow-Theo SR develops nausea or vomiting, particularly repetitive vomiting, or other signs or symptoms consistent with Slow-Theo SR toxicity (even if another cause may be suspected), additional doses of Slow-Theo SR should be withheld and a serum Slow-Theo SR concentration measured immediately. Patients should be instructed not to continue any dosage that causes adverse effects and to withhold subsequent doses until the symptoms have resolved, at which time the clinician may instruct the patient to resume the drug at a lower dosage.
Dosage Increases:
Increases in the dose of Slow-Theo SR should not be made in response to an acute exacerbation of symptoms of chronic lung disease since Slow-Theo SR provides little added benefit to inhaled beta2-selective agonists and systemically administered corticosteroids in this circumstance and increases the risk of adverse effects. A peak steady-state serum Slow-Theo SR concentration should be measured before increasing the dose in response to persistent chronic symptoms to ascertain whether an increase in dose is safe. Before increasing the Slow-Theo SR dose on the basis of a low serum concentration, the clinician should consider whether the blood sample was obtained at an appropriate time in relationship to the dose and whether the patient has adhered to the prescribed regimen.
As the rate of Slow-Theo SR clearance may be dose-dependent (i.e., steady-state serum concentrations may increase disproportionately to the increase in dose), an increase in dose based upon a sub-therapeutic serum concentration measurement should be conservative. In general, limiting dose increases to about 25% of the previous total daily dose will reduce the risk of unintended excessive increases in serum Slow-Theo SR concentration.
PRECAUTIONS
General:
Careful consideration of the various interacting drugs and physiologic conditions that can alter Slow-Theo SR clearance and require dosage adjustment should occur prior to initiation of Slow-Theo SR therapy, prior to increases in Slow-Theo SR dose, and during follow up. The dose of Slow-Theo SR selected for initiation of therapy should be low and, if tolerated, increased slowly over a period of a week or longer with the final dose guided by monitoring serum Slow-Theo SR concentrations and the patient's clinical response.
Monitoring Serum Slow-Theo SR Concentrations:
Serum Slow-Theo SR concentration measurements are readily available and should be used to determine whether the dosage is appropriate. Specifically, the serum Slow-Theo SR concentration should be measured as follows:
- When initiating therapy to guide final dosage adjustment after titration.
- Before making a dose increase to determine whether the serum concentration is sub-therapeutic in a patient who continues to be symptomatic.
- Whenever signs or symptoms of Slow-Theo SR toxicity are present.
- Whenever there is a new illness, worsening of a chronic illness or a change in the patient's treatment regimen that may alter Slow-Theo SR clearance (e.g., fever >102°F sustained for ≥24 hours, hepatitis, or drugs listed in Table II are added or discontinued).
Effects on Laboratory Tests:
As a result of its pharmacological effects, Slow-Theo SR at serum concentrations within the 10-20 mcg/mL range modestly increases plasma glucose, uric acid (from a mean of 4 mg/dl to 6 mg/dl), free fatty acids (from a mean of 451 μεq/l to 800 μεq/l, total cholesterol (from a mean of 140 vs 160 mg/dl), HDL (from a mean of 36 to 50 mg/dl), HDL/LDL ratio (from a mean of 0.5 to 0.7), and urinary free cortisol excretion (from a mean of 44 to 63 mcg/24 hr). Slow-Theo SR at serum concentrations within the 10-20 mcg/mL range may also transiently decrease serum concentrations of triiodothyronine (144 before, 131 after one week and 142 ng/dl after 4 weeks of Slow-Theo SR). The clinical importance of these changes should be weighed against the potential therapeutic benefit of Slow-Theo SR in individual patients.
Information for Patients:
The patient (or parent/care giver) should be instructed to seek medical advice whenever nausea, vomiting, persistent headache, insomnia or rapid heart beat occurs during treatment with Slow-Theo SR, even if another cause is suspected. The patient should be instructed to contact their clinician if they develop a new illness, especially if accompanied by a persistent fever, if they experience worsening of a chronic illness, if they start or stop smoking cigarettes or marijuana, or if another clinician adds a new medication or discontinues a previously prescribed medication. Patients should be instructed to inform all clinicians involved in their care that they are taking Slow-Theo SR, especially when a medication is being added or deleted from their treatment. Patients should be instructed to not alter the dose, timing of the dose, or frequency of administration without first consulting their clinician. If a dose is missed, the patient should be instructed to take the next dose at the usually scheduled time and to not attempt to make up for the missed dose.
When prescribing administration by the sprinkle method, details of the proper technique should be explained to the patient.
Drug Interactions:
Slow-Theo SR interacts with a wide variety of drugs. The interaction may be pharmacodynamic, i.e., alterations in the therapeutic response to Slow-Theo SR or another drug or occurrence of adverse effects without a change in serum Slow-Theo SR concentration. More frequently, however, the interaction is pharmacokinetic, i.e., the rate of Slow-Theo SR clearance is altered by another drug resulting in increased or decreased serum Slow-Theo SR concentrations. Slow-Theo SR only rarely alters the pharmacokinetics of other drugs.
The drugs listed in Table II have the potential to produce clinically significant pharmacodynamic or pharmacokinetic interactions with Slow-Theo SR. The information in the “Effect” column of Table II assumes that the interacting drug is being added to a steady-state Slow-Theo SR regimen. If Slow-Theo SR is being initiated in a patient who is already taking a drug that inhibits Slow-Theo SR clearance, the dose of Slow-Theo SR required to achieve a therapeutic serum Slow-Theo SR concentration will be smaller. Conversely, if Slow-Theo SR is being initiated in a patient who is already taking a drug that enhances Slow-Theo SR clearance (e.g., rifampin), the dose of Slow-Theo SR required to achieve a therapeutic serum Slow-Theo SR concentration will be larger. Discontinuation of a concomitant drug that increases Slow-Theo SR clearance will result in accumulation of Slow-Theo SR to potentially toxic levels, unless the Slow-Theo SR dose is appropriately reduced. Discontinuation of a concomitant drug that inhibits Slow-Theo SR clearance will result in decreased serum Slow-Theo SR concentrations, unless the Slow-Theo SR dose is appropriately increased. The drugs listed in Table III have either been documented not to interact with Slow-Theo SR or do not produce a clinically significant interaction (i.e., <15% change in Slow-Theo SR clearance).The listing of drugs in Tables II and III are current as of February 9, 1995. New interactions are continuously being reported for Slow-Theo SR, especially with new chemical entities. The clinician should not assume that a drug does not interact with Slow-Theo SR if it is not listed in Table II. Before addition of a newly available drug in a patient receiving Slow-Theo SR, the package insert of the new drug and/or the medical literature should be consulted to determine if an interaction between the new drug and Slow-Theo SR has been reported.
| * Refer to PRECAUTIONS, Drug Interactions for further information regarding table. | ||
| ** Average effect on steady state Slow-Theo SR concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum Slow-Theo SR concentration than the value listed. | ||
| Drug | Type of Interaction | Effect** |
|---|---|---|
| Adenosine | Slow-Theo SR blocks adenosine receptors. | Higher doses of adenosine may be required to achieve desired effect. |
| Alcohol | A single large dose of alcohol (3 mL/kg of whiskey) decreases Slow-Theo SR clearance for up to 24 hours. | 30% increase |
| Allopurinol | Decreases Slow-Theo SR clearance at allopurinol doses ≥600 mg/day. | 25% increase |
| Aminoglutethimide | Increases Slow-Theo SR clearance by induction of microsomal enzyme activity. | 25% decrease |
| Carbamazepine | Similar to aminoglutethimide. | 30% decrease |
| Cimetidine | Decreases Slow-Theo SR clearance by inhibiting cytochrome P450 1A2. | 70% increase |
| Ciprofloxacin | Similar to cimetidine. | 40% increase |
| Clarithromycin | Similar to erythromycin. | 25% increase |
| Diazepam | Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while Slow-Theo SR blocks adenosine receptors. | Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of Slow-Theo SR without reduction of diazepam dose may result in respiratory depression. |
| Disulfiram | Decreases Slow-Theo SR clearance by inhibiting hydroxylation and demethylation. | 50% increase |
| Enoxacin | Similar to cimetidine. | 300% increase |
| Ephedrine | Synergistic CNS effects. | Increased frequency of nausea, nervousness, and insomnia. |
| Erythromycin | Erythromycin metabolite decreases Slow-Theo SR clearance by inhibiting cytochrome P450 3A3. | 35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount. |
| Estrogen | Estrogen containing oral contraceptives decrease Slow-Theo SR clearance in a dose-dependent fashion. The effect of progesterone on Slow-Theo SR clearance is unknown. | 30% increase |
| Flurazepam | Similar to diazepam. | Similar to diazepam. |
| Fluvoxamine | Similar to cimetidine. | Similar to cimetidine. |
| Halothane | Halothane sensitizes the myocardium. to catecholamines, Slow-Theo SR increases release of endogenous catecholamines. | Increased risk of ventricular arrhythmias. |
| Interferon, human recombinant alpha-A | Decreases Slow-Theo SR clearance. | 100% increase |
| Isoproterenol (IV) | Increases Slow-Theo SR clearance. | 20% decrease |
| Ketamine | Pharmacologic seizure threshold. | May lower Slow-Theo SR |
| Lithium | Slow-Theo SR increases renal lithium clearance. | Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%. |
| Lorazepam | Similar to diazepam. | Similar to diazepam. |
| Methotrexate (MTX) | Decreases Slow-Theo SR clearance. | 20% increase after low dose MTX, higher dose MTX may have a greater effect. |
| Mexiletine | Similar to disulfiram. | 80% increase |
| Midazolam | Similar to diazepam. | Similar to diazepam. |
| Moricizine | Increases Slow-Theo SR clearance. | 25% decrease |
| Pancuronium | Slow-Theo SR may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. | Larger dose of pancuronium may be required to achieve neuromuscular blockade. |
| Pentoxifylline | Decreases Slow-Theo SR clearance. | 30% increase |
| Phenobarbital (PB) | Similar to aminoglutethimide. | 25% decrease after two weeks of concurrent PB. |
| Phenytoin | Phenytoin increases Slow-Theo SR clearance by increasing microsomal enzyme activity. Slow-Theo SR decreases phenytoin absorption. | Serum Slow-Theo SR and phenytoin concentrations decrease about 40%. |
| Propafenone | Decreases Slow-Theo SR clearance and pharmacologic interaction. | 40% increase. Beta-2 blocking effect may decrease efficacy of Slow-Theo SR. |
| Propranolol | Similar to cimetidine and pharmacologic interaction. | 100% increase. Beta-2 blocking effect may decrease efficacy of Slow-Theo SR. |
| Rifampin | Increases Slow-Theo SR clearance by increasing cytochrome P450 1A2 and 3A3 activity. | 20-40% decrease |
| Sulfinpyrazone | Increases Slow-Theo SR clearance by increasing demethylation and hydroxylation. Decreases renal clearance of Slow-Theo SR. | 20% decrease |
| Tacrine | Similar to cimetidine, also increases renal clearance of Slow-Theo SR. | 90% increase |
| Thiabendazole | Decreases Slow-Theo SR clearance. | 190% increase |
| Ticlopidine | Decreases Slow-Theo SR clearance. | 60% increase |
| Troleandomycin | Similar to erythromycin. | 33-100% increase depending on troleandomycin dose. |
| Verapamil | Similar to disulfiram. | 20% increase |
| * Refer to PRECAUTIONS, Drug Interactions for information regarding table. | |||
| albuterol, | diltiazem | medroxyprogesterone | roxithromycin |
| systemic and inhaled | dirithromycin | methylprednisolone | sorbitol |
| amoxicillin | enflurane | metronidazole | (purgative doses |
| ampicillin, | famotidine | metoprolol | do not inhibit |
| with or without | felodipine | nadolol | theophylline |
| sulbactam | finasteride | nifedipine | absorption) |
| atenolol | hydrocortisone | nizatidine | sucralfate |
| azithromycin | isoflurane | norfloxacin | terbutaline, systemic |
| caffeine, | isoniazid | ofloxacin | terfenadine |
| dietary ingestion | isradipine | omeprazole | tetracycline |
| cefaclor | influenza vaccine | prednisone, | tocainide |
| co-trimoxazole | ketoconazole | prednisolone | |
| (trimethoprim and | lomefloxacin | ranitidine | |
| sulfamethoxazole) | mebendazole | rifabutin | |
The Effect of Other Drugs on Slow-Theo SR Serum Concentration Measurements: Most serum Slow-Theo SR assays in clinical use are immunoassays which are specific for Slow-Theo SR. Other xanthines such as caffeine, dyphylline, and pentoxifylline are not detected by these assays. Some drugs (e.g.,cefazolin, cephalothin), however, may interfere with certain HPLC techniques. Caffeine and xanthine metabolites in neonates or patients with renal dysfunction may cause the reading from some dry reagent office methods to be higher than the actual serum Slow-Theo SR concentration.
Drug-Food: Taking Slow-Theo SR Extended-release Capsules immediately after a high-fat content meal such as 8 ounces whole milk, one fried egg, one slice of Canadian bacon, one English muffin with butter, 4 ounces hash brown potatoes, one slice of American cheese (about 240 calories, including approximately 27 g of fat) may result in an increase in the Cmax, but with no significant difference in the extent of absorption. The influence of the type and amount of other foods, as well as the time interval between drug and food, has not been studied.
Carcinogenesis, Mutagenesis, and Impairment of Fertility:
Long term carcinogenicity studies have been carried out in mice (oral doses 30-150 mg/kg) and rats (oral doses 5-75 mg/kg). Results are pending.
Slow-Theo SR has been studied in Ames salmonella, in vivo and in vitro cytogenetics, micronucleus and Chinese hamster ovary test systems and has not been shown to be genotoxic. In a 14 week continuous breeding study, Slow-Theo SR, administered to mating pairs of B6C3F1 mice at oral doses of 120, 270 and 500 mg/kg (approximately 1.0- 3.0 times the human dose on a mg/m2 basis) impaired fertility, as evidenced by decreases in the number of live pups per litter, decreases in the mean number of litters per fertile pair, and increases in the gestation period at the high dose as well as decreases in the proportion of pups born alive at the mid and high dose. In 13 week toxicity studies, Slow-Theo SR was administered to F344 rats and B6C3F1 mice at oral doses of 40-300 mg/kg (approximately 2.0 times the human dose on a mg/m2 basis). At the high dose, systemic toxicity was observed in both species including decreases in testicular weight.
Pregnancy:
CATEGORY C : There are no adequate and well controlled studies in pregnant women. Additionally, there are no teratogenicity studies in non-rodents. Slow-Theo SR was not shown to be teratogenic in CD-1 mice at oral doses up to 400 mg/kg, approximately 2.0 times the human dose on a mg/m2 basis or in CD-1 rats at oral doses up to 260 mg/kg, approximately 3.0 times the recommended human dose on a mg/m2 basis. At a dose of 220 mg/kg, embryotoxicity was observed in rats in the absence of maternal toxicity.
Nursing Mothers:
Slow-Theo SR is excreted into breast milk and may cause irritability or other signs of mild toxicity in nursing human infants. The concentration of Slow-Theo SR in breast milk is about equivalent to the maternal serum concentration. An infant ingesting a liter of breast milk containing 10-20 mcg/mL of Slow-Theo SR day is likely to receive 10-20 mg of Slow-Theo SR per day. Serious adverse effects in the infant are unlikely unless the mother has toxic serum Slow-Theo SR concentrations.
Pediatric Use:
Slow-Theo SR is safe and effective for the approved indications in pediatric patients. The maintenance dose of Slow-Theo SR must be selected with caution in pediatric patients since the rate of Slow-Theo SR clearance is highly variable across the age range of neonates to adolescents.
Geriatric Use:
Elderly patients are at significantly greater risk of experiencing serious toxicity from Slow-Theo SR than younger patients due to pharmacokinetic and pharmacodynamic changes associated with aging. Slow-Theo SR clearance is reduced in patients greater than 60 years of age, resulting in increased serum Slow-Theo SR concentrations in response to a given Slow-Theo SR dose. Protein binding may be decreased in the elderly resulting in a larger proportion of the total serum Slow-Theo SR concentration in the pharmacologically active unbound form. Elderly patients also appear to be more sensitive to the toxic effects of Slow-Theo SR after chronic overdosage than younger patients. For these reasons, the maximum daily dose of Slow-Theo SR in patients greater than 60 years of age ordinarily should not exceed 400 mg/day unless the patient continues to be symptomatic and the peak steady state serum Slow-Theo SR concentration is <10 mcg/mL. Slow-Theo SR doses greater than 400 mg/d should be prescribed with caution in elderly patients.
ADVERSE REACTIONS
Adverse reactions associated with Slow-Theo SR are generally mild when peak serum Slow-Theo SR concentrations are <20 mcg/mL and mainly consist of transient caffeine-like adverse effects such as nausea, vomiting, headache, and insomnia. When peak serum Slow-Theo SR concentrations exceed 20 mcg/mL, however, Slow-Theo SR produces a wide range of adverse reactions including persistent vomiting, cardiac arrhythmias, and intractable seizures which can be lethal. The transient caffeine-like adverse reactions occur in about 50% of patients when Slow-Theo SR therapy is initiated at doses higher than recommended initial doses (e.g.,>300 mg/day in adults and >12 mg/kg/day in children beyond >1 year of age). During the initiation of Slow-Theo SR therapy, caffeine-like adverse effects may transiently alter patient behavior, especially in school age children, but this response rarely persists. Initiation of Slow-Theo SR therapy at a low dose with subsequent slow titration to a predetermined age-related maximum dose will significantly reduce the frequency of these transient adverse effects. In a small percentage of patients (<3% of children and <10% of adults) the caffeine-like adverse effects persist during maintenance therapy, even at peak serum Slow-Theo SR concentrations within the therapeutic range (i.e., 10-20 mcg/mL). Dosage reduction may alleviate the caffeine-like adverse effects in these patients, however, persistent adverse effects should result in a reevaluation of the need for continued Slow-Theo SR therapy and the potential therapeutic benefit of alternative treatment.
Other adverse reactions that have been reported at serum Slow-Theo SR concentrations <20 mcg/mL include diarrhea, irritability, restlessness, fine skeletal muscle tremors, and transient diuresis. In patients with hypoxia secondary to COPD, multifocal atrial tachycardia and flutter have been reported at serum Slow-Theo SR concentrations ≥15 mcg/mL. There have been a few isolated reports of seizures at serum Slow-Theo SR concentrations <20 mcg/mL in patients with an underlying neurological disease or in elderly patients. The occurrence of seizures in elderly patients with serum Slow-Theo SR concentrations <20 mcg/mL may be secondary to decreased protein binding resulting in a larger proportion of the total serum Slow-Theo SR concentration in the pharmacologically active unbound form. The clinical characteristics of the seizures reported in patients with serum Slow-Theo SR concentrations <20 mcg/mL have generally been milder than seizures associated with excessive serum Slow-Theo SR concentrations resulting from an overdose (i.e. they have generally been transient, often stopped without anticonvulsant therapy, and did not result in neurological residua).
| Percentage of patients reported | ||||||
| with sign or symptom | ||||||
| Acute Overdose | Chronic Overdosage | |||||
| (Large Single Ingestion) | (Multiple Excessive Doses) | |||||
| Sign/Symptom | Study 1 | Study 2 | Study 1 | Study 2 | ||
| (n=157) | (n=14) | (n=92) | (n=102) | |||
| * These data are derived from two studies in patients with serum Slow-Theo SR concentrations >30 mcg/mL. In the first study (Study #1 - Shanon, Ann Intern Med 1993;119:1161-67), data were prospectively collected from 249 consecutive cases of Slow-Theo SR toxicity referred to a regional poison center for consultation. In the second study (Study #2 - Sessler, Am J Med 1990;88:567-76), data were retrospectively collected from 116 cases with serum Slow-Theo SR concentrations >30 mcg/mL among 6000 blood samples obtained for measurement of serum Slow-Theo SR concentrations in three emergency departments. Differences in the incidence of manifestations of Slow-Theo SR toxicity between the two studies may reflect sample selection as a result of study design (e.g., in Study #1, 48% of the patients had acute intoxications versus only 10% in Study #2) and different methods of reporting results. | ||||||
| ** NR = Not reported in a comparable manner. | ||||||
| Asymptomatic | NR** | 0 | NR** | 6 | ||
| Gastrointestinal | ||||||
| Vomiting | 73 | 93 | 30 | 61 | ||
| Abdominal Pain | NR** | 21 | NR** | 12 | ||
| Diarrhea | NR** | 0 | NR** | 14 | ||
| Hematemesis | NR** | 0 | NR** | 2 | ||
| Metabolic/Other | ||||||
| Hypokalemia | 85 | 79 | 44 | 43 | ||
| Hyperglycemia | 98 | NR** | 18 | NR** | ||
| Acid/base disturbance | 34 | 21 | 9 | 5 | ||
| Rhabdomyolysis | NR** | 7 | NR** | 0 | ||
| Cardiovascular | ||||||
| Sinus tachycardia | 100 | 86 | 100 | 62 | ||
| Other supraventricular | 2 | 21 | 12 | 14 | ||
| tachycardias | ||||||
| Ventricular premature beats | 3 | 21 | 10 | 19 | ||
| Atrial fibrillation or flutter | 1 | NR** | 12 | NR** | ||
| Cardiovascular (continued) | ||||||
| Multifocal atrial tachycardia | 0 | NR** | 2 | NR** | ||
| Ventricular arrhythmias with | 7 | 14 | 40 | 0 | ||
| hemodynamic instability | ||||||
| Hypotension/shock | NR** | 21 | NR** | 8 | ||
| Neurologic | ||||||
| Nervousness | NR** | 64 | NR** | 21 | ||
| Tremors | 38 | 29 | 16 | 14 | ||
| Disorientation | NR** | 7 | NR** | 11 | ||
| Seizures | 5 | 14 | 14 | 5 | ||
| Death | 3 | 21 | 10 | 4 | ||
OVERDOSAGE
General:
The chronicity and pattern of Slow-Theo SR overdosage significantly influences clinical manifestations of toxicity, management and outcome. There are two common presentations: acute overdose, i.e., ingestion of a single large excessive dose (>10 mg/kg) as occurs in the context of an attempted suicide or isolated medication error, and (2) chronic overdosage, i.e., ingestion of repeated doses that are excessive for the patient's rate of Slow-Theo SR clearance. The most common causes of chronic Slow-Theo SR overdosage include patient or care giver error in dosing, clinician prescribing of an excessive dose or a normal dose in the presence of factors known to decrease the rate of Slow-Theo SR clearance, and increasing the dose in response to an exacerbation of symptoms without first measuring the serum Slow-Theo SR concentration to determine whether a dose increase is safe.
Severe toxicity from Slow-Theo SR overdose is a relatively rare event. In one health maintenance organization, the frequency of hospital admissions for chronic overdosage of Slow-Theo SR was about 1 per 1000 person-years exposure. In another study, among 6000 blood samples obtained for measurement of serum Slow-Theo SR concentration, for any reason, from patients treated in an emergency department, 7% were in the 20-30 mcg/mL range and 3% were >30 mcg/mL. Approximately two-thirds of the patients with serum Slow-Theo SR concentrations in the 20-30 mcg/mL range had one or more manifestations of toxicity while >90% of patients with serum Slow-Theo SR concentrations >30 mcg/mL were clinically intoxicated. Similarly, in other reports, serious toxicity from Slow-Theo SR is seen principally at serum concentrations >30 mcg/mL.Several studies have described the clinical manifestations of Slow-Theo SR overdose and attempted to determine the factors that predict life-threatening toxicity. In general, patients who experience an acute overdose are less likely to experience seizures than patients who have experienced a chronic overdosage, unless the peak serum Slow-Theo SR concentration is >100 mcg/mL. After a chronic overdosage, generalized seizures, life-threatening cardiac arrhythmias, and death may occur at serum Slow-Theo SR concentrations >30 mcg/mL. The severity of toxicity after chronic overdosage is more strongly correlated with the patient's age than the peak serum Slow-Theo SR concentration; patients >60 years are at the greatest risk for severe toxicity and mortality after a chronic overdosage. Pre-existing or concurrent disease may also significantly increase the susceptibility of a patient to a particular toxic manifestation, e.g., patients with neurologic disorders have an increased risk of seizures and patients with cardiac disease have an increased risk of cardiac arrhythmias for a given serum Slow-Theo SR concentration compared to patients without the underlying disease. The frequency of various reported manifestations of Slow-Theo SR overdose according to the mode of overdose are listed in Table IV.Other manifestations of Slow-Theo SR toxicity include increases in serum calcium, creatine kinase, myoglobin and leukocyte count, decreases in serum phosphate and magnesium, acute myocardial infarction, and urinary retention in men with obstructive uropathy. Seizures associated with serum Slow-Theo SR concentrations >30 mcg/mL are often resistant to anticonvulsant therapy and may result in irreversible brain injury if not rapidly controlled. Death from Slow-Theo SR toxicity is most often secondary to cardiorespiratory arrest and/or hypoxic encephalopathy following prolonged generalized seizures or intractable cardiac arrhythmias causing hemodynamic compromise.
Overdose Management:
General Recommendations for Patients with Symptoms of Slow-Theo SR Overdose or Serum Slow-Theo SR Concentrations >30 mcg/mL (Note: Serum Slow-Theo SR concentrations may continue to increase after presentation of the patient for medical care.
- While simultaneously instituting treatment, contact a regional poison center to obtain updated information and advice on individualizing the recommendations that follow.
- Institute supportive care, including establishment of intravenous access, maintenance of the airway, and electrocardiographic monitoring.
- Treatment of seizures Because of the high morbidity and mortality associated with theophylline-induced seizures, treatment should be rapid and aggressive. Anticonvulsant therapy should be initiated with an intravenous benzodiazepine, e.g., diazepam, in increments of 0.1-0.2 mg/kg every 1-3 minutes until seizures are terminated. Repetitive seizures should be treated with a loading dose of phenobarbital (20 mg/kg infused over 30-60 minutes). Case reports of Slow-Theo SR overdose in humans and animal studies suggest that phenytoin is ineffective in terminating theophylline-induced seizures. The doses of benzodiazepines and phenobarbital required to terminate theophylline-induced seizures are close to the doses that may cause severe respiratory depression or respiratory arrest; the clinician should therefore be prepared to provide assisted ventilation. Elderly patients and patients with COPD may be more susceptible to the respiratory depressant effects of anticonvulsants. Barbiturate-induced coma or administration of general anesthesia may be required to terminate repetitive seizures or status epilepticus. General anesthesia should be used with caution in patients with Slow-Theo SR overdose because fluorinated volatile anesthetics may sensitize the myocardium to endogenous catecholamines released by Slow-Theo SR. Enflurane appears to less likely to be associated with this effect than halothane and may, therefore, be safer. Neuromuscular blocking agents alone should not be used to terminate seizures since they abolish the musculoskeletal manifestations without terminating seizure activity in the brain.
- Anticipate Need for Anticonvulsants In patients with Slow-Theo SR overdose who are at high risk for theophylline-induced seizures, e.g., patients with acute overdoses and serum Slow-Theo SR concentrations >100 mcg/mL or chronic overdosage in patients >60 years of age with serum Slow-Theo SR concentrations >30 mcg/mL, the need for anticonvulsant therapy should be anticipated. A benzodiazepine such as diazepam should be drawn into a syringe and kept at the patient's bedside and medical personnel qualified to treat seizures should be immediately available. In selected patients at high risk for theophylline-induced seizures, consideration should be given to the administration of prophylactic anticonvulsant therapy. Situations where prophylactic anticonvulsant therapy should be considered in high risk patients include anticipated delays in instituting methods for extracorporeal removal of Slow-Theo SR (e.g., transfer of a high risk patient from one health care facility to another for extracorporeal removal) and clinical circumstances that significantly interfere with efforts to enhance Slow-Theo SR clearance (e.g., a neonate where dialysis may not be technically feasible or a patient with vomiting unresponsive to antiemetics who is unable to tolerate multiple-dose oral activated charcoal). In animal studies, prophylactic administration of phenobarbital, but not phenytoin, has been shown to delay the onset of theophylline-induced generalized seizures and to increase the dose of Slow-Theo SR required to induce seizures (i.e., markedly increases the LD50). Although there are no controlled studies in humans, a loading dose of intravenous phenobarbital (20 mg/kg infused over 60 minutes) may delay or prevent life-threatening seizures in high risk patients while efforts to enhance Slow-Theo SR clearance are continued. Phenobarbital may cause respiratory depression, particularly in elderly patients and patients with COPD.
- Treatment of cardiac arrhythmias Sinus tachycardia and simple ventricular premature beats are not harbingers of life-threatening arrhythmias, they do not require treatment in the absence of hemodynamic compromise, and they resolve with declining serum Slow-Theo SR concentrations. Other arrhythmias, especially those associated with hemodynamic compromise, should be treated with antiarrhythmic therapy appropriate for the type of arrhythmia.
- Gastrointestinal decontamination Oral activated charcoal (0.5 g/kg up to 20 g and repeat at least once 1-2 hours after the first dose) is extremely effective in blocking the absorption of Slow-Theo SR throughout the gastrointestinal tract, even when administered several hours after ingestion. If the patient is vomiting, the charcoal should be administered through a nasogastric tube or after administration of an antiemetic. Phenothiazine antiemetics such as prochlorperazine or perphenazine should be avoided since they can lower the seizure threshold and frequently cause dystonic reactions. A single dose of sorbitol may be used to promote stooling to facilitate removal of Slow-Theo SR bound to charcoal from the gastrointestinal tract. Sorbitol, however, should be dosed with caution since it is a potent purgative which can cause profound fluid and electrolyte abnormalities, particularly after multiple doses. Commercially available fixed combinations of liquid charcoal and sorbitol should be avoided in young children and after the first dose in adolescents and adults since they do not allow for individualization of charcoal and sorbitol dosing. Ipecac syrup should be avoided in Slow-Theo SR overdoses. Although ipecac induces emesis, it does not reduce the absorption of Slow-Theo SR unless administered within 5 minutes of ingestion and even then is less effective than oral activated charcoal. Moreover, ipecac induced emesis may persist for several hours after a single dose and significantly decrease the retention and the effectiveness of oral activated charcoal.
- Serum Slow-Theo SR Concentration Monitoring The serum Slow-Theo SR concentration should be measured immediately upon presentation, 2-4 hours later, and then at sufficient intervals, e.g., every 4 hours, to guide treatment decisions and to assess the effectiveness of therapy. Serum Slow-Theo SR concentrations may continue to increase after presentation of the patient for medical care as a result of continued absorption of Slow-Theo SR from the gastrointestinal tract. Serial monitoring of serum Slow-Theo SR serum concentrations should be continued until it is clear that the concentration is no longer rising and has returned to non-toxic levels.
- General Monitoring Procedures Electrocardiographic monitoring should be initiated on presentation and continued until the serum Slow-Theo SR level has returned to a non-toxic level. Serum electrolytes and glucose should be measured on presentation and at appropriate intervals indicated by clinical circumstances. Fluid and electrolyte abnormalities should be promptly corrected. Monitoring and treatment should be continued until the serum concentration decreases below 20 mcg/mL.
- Enhance clearance of Slow-Theo SR Multiple-dose oral activated charcoal (e.g., 0.5 mg/kg up to 20 g, every two hours) increases the clearance of Slow-Theo SR at least twofold by adsorption of Slow-Theo SR secreted into gastrointestinal fluids. Charcoal must be retained in, and pass through, the gastrointestinal tract to be effective; emesis should therefore be controlled by administration of appropriate antiemetics. Alternatively, the charcoal can be administered continuously through a nasogastric tube in conjunction with appropriate antiemetics. A single dose of sorbitol may be administered with the activated charcoal to promote stooling to facilitate clearance of the adsorbed Slow-Theo SR from the gastrointestinal tract. Sorbitol alone does not enhance clearance of Slow-Theo SR and should be dosed with caution to prevent excessive stooling which can result in severe fluid and electrolyte imbalances. Commercially available fixed combinations of liquid charcoal and sorbitol should be avoided in young children and after the first dose in adolescents and adults since they do not allow for individualization of charcoal and sorbitol dosing. In patients with intractable vomiting, extracorporeal methods of Slow-Theo SR removal should be instituted.
Specific Recommendations:
Acute Overdose
- Serum Concentration >20<30 mcg/mL
- Administer a single dose of oral activated charcoal.
- Monitor the patient and obtain a serum Slow-Theo SR concentration in 2-4 hours to insure that the concentration is not increasing.
- Serum Concentration >30<100 mcg/mL
- Administer multiple dose oral activated charcoal and measures to control emesis.
- Monitor the patient and obtain serial Slow-Theo SR concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.
- Institute extracorporeal removal if emesis, seizures, or cardiac arrhythmias cannot be adequately controlled.
- Serum Concentration >100 mcg/mL
- Consider prophylactic anticonvulsant therapy.
- Administer multiple-dose oral activated charcoal and measures to control emesis.
- Consider extracorporeal removal, even if the patient has not experienced a seizure.
- Monitor the patient and obtain serial Slow-Theo SR concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.
Chronic Overdosage
- Serum Concentration >20<30 mcg/mL (with manifestations of Slow-Theo SR toxicity)
- Administer a single dose of oral activated charcoal.
- Monitor the patient and obtain a serum Slow-Theo SR concentration in 2-4 hours to insure that the concentration is not increasing.
- Serum Concentration >30 mcg/mL in patients <60 years of age
- Administer multiple-dose oral activated charcoal and measures to control emesis.
- Monitor the patient and obtain serial Slow-Theo SR concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.
- Institute extracorporeal removal if emesis, seizures, or cardiac arrhythmias cannot be adequately controlled.
- Serum Concentration >30 mcg/mL in patients ≥60 years of age.
- Consider prophylactic anticonvulsant therapy.
- Administer multiple-dose oral activated charcoal and measures to control emesis.
- Consider extracorporeal removal even if the patient has not experienced a seizure.
- Monitor the patient and obtain serial Slow-Theo SR concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.
Extracorporeal Removal:
Increasing the rate of Slow-Theo SR clearance by extracorporeal methods may rapidly decrease serum concentrations, but the risks of the procedure must be weighed against the potential benefit. Charcoal hemoperfusion is the most effective method of extracorporeal removal, increasing Slow-Theo SR clearance up to six fold, but serious complications, including hypotension, hypocalcemia, platelet consumption and bleeding diatheses may occur. Hemodialysis is about as efficient as multiple-dose oral activated charcoal and has a lower risk of serious complications than charcoal hemoperfusion. Hemodialysis should be considered as an alternative when charcoal hemoperfusion is not feasible and multiple-dose oral charcoal is ineffective because of intractable emesis. Serum Slow-Theo SR concentrations may rebound 5-10 mcg/mL after discontinuation of charcoal hemoperfusion or hemodialysis due to redistribution of Slow-Theo SR from the tissue compartment. Peritoneal dialysis is ineffective for Slow-Theo SR removal; exchange transfusions in neonates have been minimally effective.
DOSAGE AND ADMINISTRATION
General Considerations:
Taking Slow-Theo SR Extended-release Capsules immediately after a high-fat content meal may alter its rate of absorption. However, the differences are usually small and Slow-Theo SR Extended-release Capsules may normally be administered without regard to meals.
The steady-state peak serum Slow-Theo SR concentration is a function of the dose, the dosing interval, and the rate of Slow-Theo SR absorption and clearance in the individual patient. Because of marked individual differences in the rate of Slow-Theo SR clearance, the dose required to achieve a peak serum Slow-Theo SR concentration in the 10-20 mcg/mL range varies fourfold among otherwise similar patients in the absence of factors known to alter Slow-Theo SR clearance (e.g., 400-1600 mg/day in adults <60 years old and 10-36 mg/kg/day in children 1-9 years old). For a given population there is no single Slow-Theo SR dose that will provide both safe and effective serum concentrations for all patients. Administration of the median Slow-Theo SR dose required to achieve a therapeutic serum Slow-Theo SR concentration in a given population may result in either sub-therapeutic or potentially toxic serum Slow-Theo SR concentrations in individual patients. For example, at a dose of 900 mg/d in adults <60 years or 22 mg/kg/d in children 1-9 years, the steady-state peak serum Slow-Theo SR concentration will be <10 mcg/mL in about 30% of patients, 10-20 mcg/mL in about 50% and 20-30 mcg/mL in about 20% of patients. The dose of Slow-Theo SR must be individualized on the basis of peak serum Slow-Theo SR concentration measurements in order to achieve a dose that will provide maximum potential benefit with minimal risk of adverse effects. Transient caffeine-like adverse effects and excessive serum concentrations in slow metabolizers can be avoided in most patients by starting with a sufficiently low dose and slowly increasing the dose, if judged to be clinically indicated, in small increments. Dose increases should only be made if the previous dosage is well tolerated and at intervals of no less than 3 days to allow serum Slow-Theo SR concentrations to reach the new steady state. Dosage adjustment should be guided by serum Slow-Theo SR concentration measurement. Health care providers should instruct patients and care givers to discontinue any dosage that causes adverse effects, to withhold the medication until these symptoms are gone and to then resume therapy at a lower, previously tolerated dosage. If the patient's symptoms are well controlled, there are no apparent adverse effects, and no intervening factors that might alter dosage requirements, serum Slow-Theo SR concentrations should be monitored at 6 month intervals for rapidly growing children and at yearly intervals for all others. In acutely ill patients, serum Slow-Theo SR concentrations should be monitored at frequent intervals, e.g., every 24 hours. Theophylline distributes poorly into body fat, therefore, mg/kg dose should be calculated on the basis of ideal body weight. Table V contains Slow-Theo SR dosing titration schema recommended for patients in various age groups and clinical circumstances. Table VI contains recommendations for Slow-Theo SR dosage adjustment based upon serum Slow-Theo SR concentrations. Application of these general dosing recommendations to individual patients must take into account the unique clinical characteristics of each patient. In general, these recommendations should serve as the upper limit for dosage adjustments in order to decrease the risk of potentially serious adverse events associated with unexpected large increases in serum Slow-Theo SR concentration.
| * Patients with more rapid metabolism, clinically identified by higher than average dose requirements, should receive a smaller dose more frequently to prevent breakthrough symptoms resulting from low trough concentrations before the next dose. A reliably absorbed slow-release formulation will decrease fluctuations and permit longer dosing intervals. | |||
| A. Children (1-15 years) and adults (16-60 years) without risk factors for impaired clearance. | |||
| Titration Step | Children < 45 kg | Children > 45 kg and adults | |
| 1 Starting Dosage | 12-14 mg/kg/day up to a maximum | 300 mg/day divided | |
| of 300 mg/day divided Q8-12 hrs* | Q8-12 hrs* | ||
| 2 After 3 days, | 16 mg/kg/day up to a maximum | 400 mg/day divided | |
| if tolerated, | of 400 mg/day divided Q8-12 hrs* | Q8- 12 hrs* | |
| increase dose to: | |||
| 3 After 3 more days, if | 20 mg/kg/day up to a maximum | 600 mg/day divided | |
| tolerated and if needed, | of 600 mg/day divided Q8-12 hrs* | Q8-12 hrs* | |
| increase dose to: | |||
| B. | Once-Daily Dosing: | ||
| The slow absorption rate of this preparation may allow once-daily administration in adult nonsmokers with appropriate total body clearance and other patients with low dosage requirements. Once-daily dosing should be considered only after the patient has been gradually and satisfactorily treated to therapeutic levels with q12h dosing. Once-daily dosing should be based on the dosing guidelines in Table V and Table VI, and should be initiated at the end of the last q12h dosing interval. The trough concentration (Cmin) obtained following conversion to once-daily dosing may be lower (especially in high clearance patients) and the peak concentration (Cmax) may be higher (especially in low clearance patients) than that obtained with q12h dosing. If symptoms recur, or signs of toxicity appear during the once-daily dosing interval, dosing on the q12h basis should be reinstituted. It is essential that serum Slow-Theo SR concentrations be monitored before and after transfer to once-daily dosing. Food and posture, along with changes associated with circadian rhythm, may influence the rate of absorption and/or clearance rates of Slow-Theo SR from extended-release dosage forms administered at night. The exact relationship of these and other factors to nighttime serum concentrations and the clinical significance of such findings require additional study. Therefore, it is not recommended that Slow-Theo SR Extended-release Capsules when used as a once-a-day product, be administered at night. | |||
| C. | Patients With Risk Factors For Impaired Clearance, The Elderly (>60 Years), And Those In Whom It Is Not Feasible To Monitor Serum Slow-Theo SR Concentrations: | ||
| In children 1-15 years of age, the final Slow-Theo SR dose should not exceed 16 mg/kg/day up to a maximum of 400 mg/day in the presence of risk factors for reduced Slow-Theo SR clearance or if it is not feasible to monitor serum Slow-Theo SR concentrations. In adolescents ≥16 years and adults, including the elderly, the final Slow-Theo SR dose should not exceed 400 mg/day in the presence of risk factors for reduced Slow-Theo SR clearance or if it is not feasible to monitor serum Slow-Theo SR concentrations. | |||
| Peak Serum Concentration | Dosage Adjustment |
|---|---|
| ¶ Dose reduction and/or serum Slow-Theo SR concentration measurement is indicated whenever adverse effects are present, physiologic abnormalities that can reduce Slow-Theo SR clearance occur (e.g., sustained fever), or a drug that interacts with Slow-Theo SR is added or discontinued. | |
| <9.9 mcg/mL | If symptoms are not controlled and current dosage is tolerated, increase dose about 25%. Recheck serum concentration after three days for further dosage adjustment. |
| 10 to 14.9 mcg/mL | If symptoms are controlled and current dosage is tolerated, maintain dose and recheck serum concentration at 6-12 month intervals.¶ If symptoms are not controlled and current dosage is tolerated consider adding additional medication(s) to treatment regimen. |
| 15-19.9 mcg/mL | Consider 10% decrease in dose to provide greater margin of safety even if current dosage is tolerated.¶ |
| 20-24.9 mcg/mL | Decrease dose by 25% even if no adverse effects are present. Recheck serum concentration after 3 days to guide further dosage adjustment. |
| 25-30 mcg/mL | Skip next dose and decrease subsequent doses at least 25% even if no adverse effects are present. Recheck serum concentration after 3 days to guide further dosage adjustment. If symptomatic, consider whether overdose treatment is indicated. |
| >30 mcg/mL | Treat overdose as indicated. If Slow-Theo SR is subsequently resumed, decrease dose by at least 50% and recheck serum concentration after 3 days to guide further dosage adjustment. |
Sprinkling Contents on Food
Slow-Theo SR Extended-release Capsules may be administered by carefully opening the capsule and sprinkling the beaded contents on a spoonful of soft food such as applesauce or pudding; the soft food should be swallowed immediately without chewing and followed with a glass of cool water or juice to ensure complete swallowing of the beads. It is recommended that the food used should not be hot and should be soft enough to be swallowed without chewing. Any bead/food mixture should be used immediately and not stored for future use. SUBDIVIDING THE CONTENTS OF A CAPSULE IS NOT RECOMMENDED.
HOW SUPPLIED
Slow-Theo SR Extended-release Capsules USP are available as 125 mg, 200 mg, or 300 mg and have the following identification characteristics:
Slow-Theo SR Extended-release 125 mg clear/clear capsule, with off-white seeds, and imprint: IL/3638.
Available in bottles of 100 (NDC 0258-3638-01).Theophylline Extended-release 200 mg clear/opaque white capsule, with off-white seeds, and imprint: IL/3634.
Available in bottles of 100 (NDC 0258-3634-01).Theophylline Extended-release 300 mg opaque white/clear capsule, with off-white seeds, and imprint: IL/3625.
Available in bottles of 100 (NDC 0258-3625-01).
STORAGE: Store at controlled room temperature 15° - 30°C (59°- 86°F).
Dispense in a tight container as defined in the USP.
Keep this and all medications out of the reach of children. Inwood Laboratories, Inc.
Subsidiary of FOREST LABORATORIES, INC.
Inwood, New York 11096MG #9933 (06)
Rev. 03/05
Slow-Theo SR pharmaceutical active ingredients containing related brand and generic drugs:
Slow-Theo SR available forms, composition, doses:
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.