A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Meridia Side Effects, and Drug Interactions - Sibutramine Hcl
Meridia Side Effects, and Drug Interactions - Sibutramine Hcl
SIDE EFFECTS
In placebo-controlled studies, 9% of patients treated with MERIDIA (n=2068) and 7% of patients treated with placebo (n=884) withdrew for adverse events.
In placebo-controlled studies, the most common events were dry mouth, anorexia, insomnia, constipation and headache. Adverse events in these studies occurring in ≥1% of MERIDIA treated patients and more frequently than in the placebo group are shown in the following table.
|
BODYSYSTEM
Adverse Event |
Obese Patients in Placebo-Controlled Studies |
|
MERIDIA® (n = 2068) |
Placebo (n = 884) |
|
% Incidence |
% Incidence |
|
BODY AS A WHOLE: |
|
|
|
Headache |
30.3 |
18.6 |
|
Back pain |
8.2 |
5.5 |
|
Flu syndrome |
8.2 |
5.8 |
|
Injury accident |
5.9 |
4.1 |
|
Asthenia |
5.9 |
5.3 |
|
Abdominal pain |
4.5 |
3.6 |
|
Chest pain |
1.8 |
1.2 |
|
Neck pain |
1.6 |
1.1 |
|
Allergic reaction |
1.5 |
0.8 |
|
CARDIOVASCULAR SYSTEM |
|
|
|
Tachycardia |
2.6 |
0.6 |
|
Vasodilation |
2.4 |
0.9 |
|
Migraine |
2.4 |
2.0 |
|
Hypertension/increased blood pressure |
2.1 |
0.9 |
|
Palpitation |
2.0 |
0.8 |
|
DIGESTIVE SYSTEM |
|
|
|
Anorexia |
13.0 |
3.5 |
|
Constipation |
11.5 |
6.0 |
|
Increased appetite |
8.7 |
2.7 |
|
Nausea |
5.9 |
2.8 |
|
Dyspepsia |
5.0 |
2.6 |
|
Gastritis |
1.7 |
1.2 |
|
Vomiting |
1.5 |
1.4 |
|
Rectal disorder |
1.2 |
0.5 |
|
METABOLIC & NUTRITIONAL |
|
|
|
Thirst |
1.7 |
0.9 |
|
Generalized edema |
1.2 |
0.8 |
|
MUSCULOSKELETAL SYSTEM |
|
|
|
Arthralgia |
5.9 |
5.0 |
|
Myalgia |
1.9 |
1.1 |
|
Tenosynovitis |
1.2 |
0.5 |
|
Joint disorder |
1.1 |
0.6 |
|
NERVOUS SYSTEM |
|
|
|
Dry mouth |
17.2 |
4.2 |
|
Insomnia |
10.7 |
4.5 |
|
Dizziness |
7.0 |
3.4 |
|
Nervousness |
5.2 |
2.9 |
|
Anxiety |
4.5 |
3.4 |
|
Depression |
4.3 |
2.5 |
|
Paresthesia |
2.0 |
0.5 |
|
Somnolence |
1.7 |
0.9 |
|
CNS stimulation |
1.5 |
0.5 |
|
Emotional lability |
1.3 |
0.6 |
|
RESPIRATORY SYSTEM |
|
|
|
Rhinitis |
10.2 |
7.1 |
|
Pharyngitis |
10.0 |
8.4 |
|
Sinusitis |
5.0 |
2.6 |
|
Cough increase |
3.8 |
3.3 |
|
Laryngitis |
1.3 |
0.9 |
|
SKIN & APPENDAGES |
|
|
|
Rash |
3.8 |
2.5 |
|
Sweating |
2.5 |
0.9 |
|
Herpes simplex |
1.3 |
1.0 |
|
Acne |
1.0 |
0.8 |
|
SPECIAL SENSES |
|
|
|
Taste perversion |
2.2 |
0.8 |
|
Ear disorder |
1.7 |
0.9 |
|
Ear pain |
1.1 |
0.7 |
|
UROGENITAL SYSTEM |
|
|
|
Dysmenorrhea |
3.5 |
1.4 |
|
Urinary tract infection |
2.3 |
2.0 |
|
Vaginal monilia |
1.2 |
0.5 |
|
Metrorrhagia |
1.0 |
0.8 |
The following additional adverse events were reported in ³ 1% of all patients who received MERIDIA in controlled and uncontrolled pre-marketing studies.
Body as a Whole: fever.
Digestive System: diarrhea, flatulence, gastroenteritis, tooth disorder.
Metabolic and Nutritional: peripheral edema.
Musculoskeletal System: arthritis.
Nervous System: agitation, leg cramps, hypertonia, thinking abnormal.
Respiratory System: bronchitis, dyspnea.
Skin and Appendages: pruritus.
Special Senses: amblyopia.
Urogenital System: menstrual disorders.
Other Adverse Events
CLINICAL STUDIES
Seizures: Convulsions were reported as an adverse event in three of 2068 (0.1%) MERIDIA treated patients and in none of 884 placebo-treated patients in placebo-controlled premarketing obesity studies. Two of the three patients with seizures had potentially predisposing factors (one had a prior history of epilepsy; one had a subsequent diagnosis of brain tumor). The incidence in all subjects who received MERIDIA (three of 4,588 subjects) was less than 0.1%.
Ecchymosis/Bleeding Disorders: Ecchymosis (bruising) was observed in 0.7% of MERIDIA treated patients and in 0.2% of placebo-treated patients in pre-marketing placebo-controlled obesity studies. One patient had prolonged bleeding of a small amount which occurred during minor facial surgery. MERIDIA may have an effect on platelet function due to its effect on serotonin uptake.
Interstitial Nephritis: Acute interstitial nephritis (confirmed by biopsy) was reported in one obese patient receiving MERIDIA during pre-marketing studies. After discontinuation of the medication, dialysis and oral corticosteroids were administered; renal function normalized. The patient made a full recovery.
Altered Laboratory Findings: Abnormal liver function tests, including increases in AST, ALT, GGT, LDH, alkaline phosphatase and bilirubin, were reported as adverse events in 1.6% of MERIDIA-treated obese patients in placebo-controlled trials compared with 0.8% of placebo patients. In these studies, potentially clinically significant values (total bilirubin ≥2 mg/dL; ALT, AST, GGT, LDH, or alkaline phosphatase ≥3x upper limit of normal) occurred in 0% (alkaline phosphatase) to 0.6% (ALT) of the MERIDIA treated patients and in none of the placebo-treated patients. Abnormal values tended to be sporadic, often diminished with continued treatment, and did not show a clear dose-response relationship.
Postmarketing Reports
Voluntary reports of adverse events temporally associated with the use of MERIDIA are listed below. It is important to emphasize that although these events occurred during treatment with MERIDIA, they may have no causal relationship with the drug. Obesity itself, concurrent disease states/risk factors, or weight reduction may be associated with an increased risk for some of these events.
Psychiatric: Cases of depression, suicidal ideation and suicide have been reported rarely in patients on sibutramine treatment. However, a relationship has not been established between the occurrence of depression and/or suicidal ideation and the use of sibutramine. If depression occurs during treatment with sibutramine, further evaluation may be necessary.
Hypersensitivity: Allergic hypersensitivity reactions ranging from mild skin eruptions and urticaria to angioedema and anaphylaxis have been reported (see "CONTRAINDICATIONS" and "PRECAUTIONS-Information For Patients", and other reports of allergic reactions listed below).
Other Postmarketing Reported Events:
Body as a Whole: anaphylactic shock, anaphylactoid reaction, chest pressure, chest tightness, facial edema, limb pain, sudden unexplained death.
Cardiovascular System: angina pectoris, atrial fibrillation, congestive heart failure, heart arrest, heart rate decreased, myocardial infarction, supraventricular tachycardia, syncope, torsade de pointes, vascular headache, ventricular tachycardia, ventricular extrasystoles, ventricular fibrillation.
Digestive System: cholecystitis, cholelithiasis, duodenal ulcer, eructation, gastrointestinal hemorrhage, increased salivation, intestinal obstruction, mouth ulcer, stomach ulcer, tongue edema.
Endocrine System: goiter, hyperthyroidism, hypothyroidism.
Hemic and Lymphatic System: anemia, leukopenia, lymphadenopathy, petechiae, thrombocytopenia.
Metabolic and Nutritional: hyperglycemia, hypoglycemia.
Musculoskeletal System: arthrosis, bursitis.
Nervous System: abnormal dreams, abnormal gait, amnesia, anger, cerebrovascular accident, concentration impaired, confusion, depression aggravated, Gilles de la Tourette´s syndrome, hypesthesia, libido decreased, libido increased, manic reaction, mood changes, nightmares, serotonin syndrome, short term memory loss, speech disorder, transient ischemic attack, tremor, twitch, vertigo.
Respiratory System: epistaxis, nasal congestion, respiratory disorder, yawn.
Skin and Appendages: alopecia, dermatitis, photosensitivity (skin), urticaria.
Special Senses: abnormal vision, blurred vision, dry eye, eye pain, increased intraocular pressure, otitis externa, otitis media, photosensitivity (eyes), tinnitus.
Urogenital System: abnormal ejaculation, hematuria, impotence, increased urinary frequency, micturition difficulty, urinary retention.
DRUG ABUSE AND DEPENDENCE
Controlled Substance
MERIDIA is controlled in Schedule IV of the Controlled Substances Act (CSA).
Abuse and Physical and Psychological Dependence
Physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse (e.g., drug development of tolerance, incrementation of doses, drug seeking behavior).
DRUG INTERACTIONS
CNS Active Drugs
The use of MERIDIA in combination with other CNS-active drugs, particularly serotonergic agents, has not been systematically evaluated. Consequently, caution is advised if the concomitant administration of MERIDIA with other centrally-acting drugs is indicated (see "CONTRAINDICATIONS" and "WARNINGS").
In patients receiving monoamine oxidase inhibitors (MAOIs) (e.g., phenelzine, selegiline) in combination with serotonergic agents (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine), there have been reports of serious, sometimes fatal, reactions ("serotonin syndrome;" see below). Because MERIDIA inhibits serotonin reuptake, MERIDIA should not be used concomitantly with a MAOI (see "CONTRAINDICATIONS"). At least 2 weeks should elapse between discontinuation of a MAOI and initiation of treatment with MERIDIA. Similarly, at least 2 weeks should elapse between discontinuation of MERIDIA and initiation of treatment with a MAOI.
The rare, but serious, constellation of symptoms termed "serotonin syndrome" has also been reported with the concomitant use of selective serotonin reuptake inhibitors and agents for migraine therapy, such as Imitrex® (sumatriptan succinate) and dihydroergotamine, certain opioids, such as dextromethorphan, meperidine, pentazocine and fentanyl, lithium, or tryptophan. Serotonin syndrome has also been reported with the concomitant use of two serotonin reuptake inhibitors. The syndrome requires immediate medical attention and may include one or more of the following symptoms: excitement, hypomania, restlessness, loss of consciousness, confusion, disorientation, anxiety, agitation, motor weakness, myoclonus, tremor, hemiballismus, hyperreflexia, ataxia, dysarthria, incoordination, hyperthermia, shivering, pupillary dilation, diaphoresis, emesis, and tachycardia.
Because MERIDIA inhibits serotonin reuptake, in general, it should not be administered with other serotonergic agents such as those listed above. However, if such a combination is clinically indicated, appropriate observation of the patient is warranted.
Drugs That May Raise Blood Pressure and/or Heart Rate: Concomitant use of MERIDIA and other agents that may raise blood pressure or heart rate have not been evaluated. These include certain decongestants, cough, cold, and allergy medications that contain agents such as ephedrine, or pseudoephedrine. Caution should be used when prescribing MERIDIA to patients who use these medications.
Drugs That Inhibit Cytochrome P450(3A4) Metabolism: In vitro studies indicated that the cytochrome P450(3A4)-mediated metabolism of sibutramine was inhibited by ketoconazole and to a lesser extent by erythromycin. Clinical interaction trials were conducted on these substrates. The potential for such interactions is described below.
Ketoconazole: Concomitant administration of 200 mg doses of ketoconazole twice daily and 20 mg sibutramine once daily for 7 days in 12 uncomplicated obese subjects resulted in moderate increases in AUC and Cmax of 58% and 36% for M1 and of 20% and 19% for M2, respectively.
Erythromycin: The steady-state pharmacokinetics of sibutramine and metabolites M1 and M2 were evaluated in 12 uncomplicated obese subjects following concomitant administration of 500 mg of erythromycin three times daily and 20 mg of sibutramine once daily for 7 days. Concomitant erythromycin resulted in small increases in the AUC (less than 14%) for M1 and M2. A small reduction in Cmax for M1 (11%) and a slight increase in Cmax for M2 (10%) were observed.
Cimetidine: Concomitant administration of cimetidine 400 mg twice daily and sibutramine 15 mg once daily for 7 days in 12 volunteers resulted in small increases in combined (M1 and M2) plasma Cmax (3.4%) and AUC (7.3%); these differences are unlikely to be of clinical significance.
Alcohol: In a double-blind, placebo-controlled, crossover study in 19 volunteers, administration of a single dose of ethanol (0.5 mL/kg) together with 20 mg of sibutramine resulted in no psychomotor interactions of clinical significance between alcohol and sibutramine. However, the concomitant use of MERIDIA and excess alcohol is not recommended.
Oral Contraceptives: The suppression of ovulation by oral contraceptives was not inhibited by MERIDIA. In a crossover study, 12 healthy female volunteers on oral steroid contraceptives received placebo in one period and 15 mg sibutramine in another period over the course of 8 weeks. No clinically significant systemic interaction was observed; therefore, no requirement for alternative contraceptive precautions are needed when patients taking oral contraceptives are concurrently prescribed sibutramine.
Drugs Highly Bound to Plasma Proteins: Although sibutramine and its active metabolites M1 and M2 are extensively bound to plasma proteins (³94%), the low therapeutic concentrations and basic characteristics of these compounds make them unlikely to result in clinically significant protein binding interactions with other highly protein bound drugs such as warfarin and phenytoin. In vitro protein binding interaction studies have not been conducted.
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