Uniphyl (Theophylline) - Side Effects and Adverse Reactions

ADVERSE REACTIONS

Adverse reactions associated with theophylline are generally mild when peak serum theophylline concentrations are <20 mcg/mL and mainly consist of transient caffeine-like adverse effects such as nausea, vomiting, headache, and insomnia. When peak serum theophylline concentrations exceed 20 mcg/mL, however, theophylline produces a wide range of adverse reactions including persistent vomiting, cardiac arrhythmias, and intractable seizures which can be lethal (see OVERDOSAGE). The transient caffeine-like adverse reactions occur in about 50% of patients when theophylline 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 theophylline therapy, caffeine-like adverse effects may transiently alter patient behavior, especially in school age children, but this response rarely persists. Initiation of theophylline 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 (see DOSAGE AND ADMINISTRATION, Table V). 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 theophylline 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 theophylline therapy and the potential therapeutic benefit of alternative treatment.

Other adverse reactions that have been reported at serum theophylline concentrations <20 mcg/mL include abdominal pain, agitation, anaphylactic reaction, anaphylactoid reaction, anxiety, cardiac arrhythmias, diarrhea, dizziness, fine skeletal muscle tremors, gastric irritation, gastroesophageal reflux, hyperuricemia, irritability, palpitations, pruritus, rash, sinus tachycardia, restlessness, transient diuresis, urinary retention and urticaria. In patients with hypoxia secondary to COPD, multifocal atrial tachycardia and flutter have been reported at serum theophylline concentrations ≥15 mcg/mL. There have been a few isolated reports of seizures at serum theophylline concentrations <20 mcg/mL in patients with an underlying neurological disease or in elderly patients. The occurrence of seizures in elderly patients with serum theophylline concentrations <20 mcg/mL may be secondary to decreased protein binding resulting in a larger proportion of the total serum theophylline concentration in the pharmacologically active unbound form. The clinical characteristics of the seizures reported in patients with serum theophylline concentrations <20 mcg/mL have generally been milder than seizures associated with excessive serum theophylline concentrations resulting from an overdose (i.e., they have generally been transient, often stopped without anticonvulsant therapy, and did not result in neurological residua).

TABLE IV. Manifestations of theophylline toxicity. *

	Percentage of patients reported with sign or symptom
Sign/Symptom	Acute Overdose		Chronic Overdosage
	(Large Single Ingestion)		(Multiple Excessive Doses)
	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 theophylline 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 theophylline 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 theophylline concentrations >30 mcg/mL among 6000 blood samples obtained for measurement of serum theophylline concentrations in three emergency departments. Differences in the incidence of manifestations of theophylline 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
tachycardias	2	21	12	14
Ventricular premature beats	3	21	10	19
Atrial fibrillation or flutter	1	NR**	12	NR**
Multifocal atrial tachycardia	0	NR**	2	NR**
Ventricular arrhythmias with hemodynamic instability	7	14	40	0
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

REPORTS OF SUSPECTED UNIPHYL SIDE EFFECTS / ADVERSE REACTIONS

Possible Uniphyl side effects / adverse reactions in 37 year old female

Reported by a consumer/non-health professional from Japan on 2011-12-09

Patient: 37 year old female

Reactions: Rhabdomyolysis

Adverse event resulted in: disablity

Suspect drug(s):
Clarithromycin
    Dosage: unk
    Administration route: Oral
    Indication: Pneumonia Mycoplasmal
    End date: 2011-11-14

Epinastine Hydrochloride
    Dosage: unk
    Administration route: Oral
    Indication: Pneumonia Mycoplasmal
    End date: 2011-11-14

Onon
    Dosage: unk
    Administration route: Oral
    Indication: Pneumonia Mycoplasmal
    End date: 2011-11-14

Uniphyl
    Dosage: unk
    Administration route: Oral
    Indication: Pneumonia Mycoplasmal
    End date: 2011-11-14

Other drugs received by patient: Acetaminophen; Empynase; Singulair; Symbicort; Huscode

Possible Uniphyl side effects / adverse reactions in 76 year old female

Reported by a pharmacist from Japan on 2012-03-06

Patient: 76 year old female weighing 70.0 kg (154.0 pounds)

Reactions: Jaundice

Adverse event resulted in: hospitalization

Suspect drug(s):
Imidafenacin
    Dosage: 0.1 mg, 1x/day
    Administration route: Oral
    Indication: Pollakiuria
    Start date: 2011-11-04
    End date: 2012-02-02

Lyrica
    Dosage: 100 mg, 1x/day
    Administration route: Oral
    Start date: 2011-01-05
    End date: 2011-04-21

Lyrica
    Dosage: 75 mg, 1x/day
    Administration route: Oral
    Indication: Neuropathy Peripheral
    Start date: 2010-12-29
    End date: 2011-01-04

Lyrica
    Dosage: 225 mg, 1x/day
    Administration route: Oral
    Start date: 2011-04-22
    End date: 2012-02-09

Rabeprazole Sodium
    Dosage: 10 mg, 1x/day
    Administration route: Oral
    Indication: Gastric Ulcer

Uniphyl
    Dosage: 100 mg, 1x/day
    Administration route: Oral
    Indication: Asthma

Urso 250
    Dosage: 100 mg, 3x/day
    Administration route: Oral
    Indication: Hepatitis C
    End date: 2012-02-16

Other drugs received by patient: Myonal; Alogliptin Benzoate; Diazepam; Prednisolone; Folic Acid; Aspara K

Possible Uniphyl side effects / adverse reactions in 71 year old female

Reported by a health professional (non-physician/pharmacist) on 2012-06-06

Patient: 71 year old female

Reactions: Lymphadenopathy, Neoplasm Malignant, Metastases TO Liver, Sepsis, Anaemia, Rectal Haemorrhage, Melaena, Metastases TO Lung

Adverse event resulted in: death, hospitalization

Suspect drug(s):
Acetaminophen
    Dosage: 4 gm (1 gm, 4 in 1 d)
    Indication: Product Used FOR Unknown Indication

Aspirin
    Dosage: 4 gm (1 gm, 4 in 1 d)
    Indication: Product Used FOR Unknown Indication

Capecitabine
    Dosage: oral
    Administration route: Oral
    Indication: Gastric Cancer

Ethamsylate (Etamsilate)
    Dosage: 2000 mg (500 mg, 4 in 1 d)
    Indication: Gastrointestinal Haemorrhage

Lansoprazole
    Dosage: 60 mg (30 mg, 2 in 1 d), oral
    Administration route: Oral
    Indication: Product Used FOR Unknown Indication

Metfformin Hydrochloride
    Dosage: 500 mg (500 mg, 1 in 1 d)
    Indication: Product Used FOR Unknown Indication

Tranexamic Acid
    Dosage: 3 gm (1 gm, 3 in 1 d),oral
    Administration route: Oral
    Indication: Haemorrhage

Uniphyl
    Dosage: 400 mg (200 mg, 1 in 1 d)
    Indication: Product Used FOR Unknown Indication