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Avandamet

  • Generic Name: rosiglitazone maleate and metformin hcl
  • Brand Name: Avandamet

Avandamet (Rosiglitazone Maleate and Metformin HCl) side effects drug center

 

PROFESSIONAL

CONSUMER

SIDE EFFECTS

Avandamet Side Effects Center

Avandamet (rosiglitazone maleate and metformin hydrochloride) is a combination of two oral diabetes medicines that help control blood sugar levels for people with type 2 diabetes who do not use daily insulin injections. Avandamet is not for treating type 1 diabetes. Common side effects of Avandamet include nausea, vomiting, stomach upset, diarrhea and metallic taste at the beginning of treatment as the body adjusts to the medication. Other side effects of Avandamet include headache, tired feeling, and cold symptoms such as stuffy nose, sneezing, sore throat.

Avandamet is generally given in divided doses with meals, with gradual dose escalation. The maximum recommended total daily dose is 8 mg rosiglitazone (taken as 4 mg twice daily) and 2,000 mg metformin (taken as 1,000 mg twice daily). Hyperglycemia (high blood sugar) may result if Avandamet is taken with: diuretics (water pills), steroids, phenothiazines, thyroid medicines, birth control pills and other hormones, seizure medicines, diet pills or medicines to treat asthma, colds or allergies. Hypoglycemia (low blood sugar) may result if Avandamet is taken with: nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin or other salicylates, sulfa drugs, monoamine oxidase inhibitors (MAOIs), beta-blockers, or probenecid. Avandamet may interact with gemfibrozil, rifampin, vancomycin, nifedipine, procainamide, quinidine, cimetidine, ranitidine, digoxin, or morphine. Tell your doctor all medications and supplements you use. Avandamet should be used only when prescribed during pregnancy. Your doctor may substitute insulin for this drug during your pregnancy. This medication passes into breast milk. Consult your doctor before breastfeeding.

Our Avandamet (rosiglitazone maleate and metformin hydrochloride) Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.

 

Avandamet Consumer Information

Get emergency medical help if you have signs of an allergic reaction (hives, itching, dizziness, rapid heartbeats, difficult breathing, swelling in your face or throat) or a severe skin reaction (fever, sore throat, burning eyes, skin pain, red or purple skin rash with blistering and peeling).

Stop using rosiglitazone and call your doctor at once if you have symptoms of liver damage: nausea, upper stomach pain, itching, loss of appetite, dark urine, clay-colored stools, or jaundice (yellowing of the skin or eyes).

Call your doctor at once if you have:

  • shortness of breath (especially when lying down), unusual tiredness, swelling, rapid weight gain;
  • chest pain or pressure, pain spreading to your jaw or shoulder, nausea, sweating;
  • pale skin, feeling light-headed or short of breath, cold hands and feet;
  • changes in your vision; or
  • sudden unusual pain in your hand, arm, or foot.

Common side effects may include:

  • headache; or
  • cold symptoms such as stuffy nose, sinus pain, sneezing, sore throat.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Read the entire detailed patient monograph for Avandamet (Rosiglitazone Maleate and Metformin HCl)

 

Avandamet Professional Information

SIDE EFFECTS

The following adverse reactions are discussed in more detail elsewhere in the labeling:

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Patients With Inadequate Glycemic Control on Diet and Exercise

Table 4 summarizes the incidence and types of adverse reactions without regard to causality reported in a controlled, 32-week, double-blind clinical trial of AVANDAMET in patients with inadequate glycemic control on diet and exercise (N = 468).

Table 4: Adverse Events (≥5% for AVANDAMET) Reported by Patients With Inadequate Glycemic Control on Diet and Exercise in a 32-Week, Double-blind Clinical Trial of AVANDAMET

Preferred Term AVANDAMET
N = 155 %		 Metformin
N = 154 %		 Rosiglitazone
N = 159 %
Nausea/vomiting 16 13 8
Diarrhea 14 21 7
Headache 11 12 10
Dyspepsia 10 8 9
Upper respiratory tract infection 9 7 8
Dizziness 8 3 5
Edema 6 3 7
Nasopharyngitis 6 5 4
Abdominal pain 5 6 7
Arthralgia 5 3 7
Loose stools 5 6 1
Constipation 5 4 6

Mild (no intervention required) to moderate (minor intervention required) symptomatic hypoglycemia was reported by 12% (18/155) of patients treated with AVANDAMET, 14/154 (9%) with metformin, and 8% (13/159) with rosiglitazone. Approximately half of these episodes were accompanied by a simultaneous capillary glucose measurement, and the rate of confirmed hypoglycemia (blood glucose ≤ 50 mg/dL) was low in this clinical trial: 0.6% (1/155) for AVANDAMET, 1.3% (2/154) for metformin, and 0% with rosiglitazone. No hypoglycemic episode led to withdrawal in patients treated with AVANDAMET, and no patients required medical intervention due to hypoglycemia.

The incidence of edema was 6% on AVANDAMET compared with 7% on rosiglitazone and 3% on metformin.

The incidence of anemia was 4% in patients treated with AVANDAMET compared with either rosiglitazone (2%) or metformin (0%).

Patients Inadequately Controlled on Rosiglitazone Monotherapy

The incidence and types of adverse events reported in controlled, 26-week clinical trials of rosiglitazone administered in combination with metformin 2,500 mg/day in comparison with adverse reactions reported in association with rosiglitazone and metformin monotherapies are shown in Table 5. Overall, the types of adverse reactions without regard to causality reported when rosiglitazone was used in combination with metformin were similar to those reported during monotherapy with rosiglitazone.

Table 5: Adverse Events (≥5% for Rosiglitazone Plus Metformin) Reported by Patients in 26-Week, Double-blind Clinical r “rials of Rosiglitazone Added to Metformin Therapy

Preferred Term Rosiglitazone + Metformin
N = 338 %		 Rosiglitazone
N = 2,526 %		 Placebo
N = 601 %		 Metformin
N = 225 %
Upper respiratory tract infection 16.0 9.9 8.7 8.9
Diarrhea 12.7 2.3 3.3 15.6
Injury 8.0 7.6 4.3 7.6
Anemia 7.1 1.9 0.7 2.2
Headache 6.5 5.9 5.0 8.9
Sinusitis 6.2 3.2 4.5 5.3
Fatigue 5.9 3.6 5.0 4.0
Back pain 5.0 4.0 3.8 4.0
Viral infection 5.0 3.2 4.0 3.6
Arthralgia 5.0 3.0 4.0 2.2

Reports of hypoglycemia in patients treated with rosiglitazone added to maximum metformin therapy in double-blind trials were more frequent (3.0%) than in patients treated with rosiglitazone (0.6%) or metformin monotherapies (1.3%) or placebo (0.2%). Overall, anemia and edema were generally mild to moderate in severity and usually did not require discontinuation of treatment with rosiglitazone.

Edema was reported in 4.8% of patients receiving rosiglitazone compared with 1.3% on placebo, and 2.2% on metformin monotherapy and 4.4% on rosiglitazone in combination with maximum doses of metformin.

Reports of anemia (7.1%) were greater in patients treated with rosiglitazone added to metformin compared with monotherapy with rosiglitazone. Lower pre-treatment hemoglobin/hematocrit levels in patients enrolled in the metformin and rosiglitazone combination therapy clinical trials may have contributed to the higher reporting rate of anemia in these trials.

Combination With Insulin

The incidence of hypoglycemia (confirmed by fingerstick blood glucose concentration ≤ 50 mg/dL) was 14% for patients on AVANDAMET plus insulin compared with 10% for patients on insulin monotherapy.

The incidence of edema was 7% when insulin was added to AVANDAMET compared with 3% with insulin monotherapy. This trial excluded patients with pre-existing heart failure or new or worsening edema on AVANDAMET. However, in 26-week, double-blind, fixed-dose trials of rosiglitazone added to insulin, edema was reported with higher frequency (rosiglitazone in combination with insulin, 14.7%; insulin, 5.4%) [see WARNINGS AND PRECAUTIONS].

In trials in which rosiglitazone was added to insulin, rosiglitazone increased the risk of congestive heart failure [see WARNINGS AND PRECAUTIONS].

In a trial in which insulin was added to AVANDAMET, no myocardial ischemia was observed in the insulin group (N = 158), and no congestive heart failure was reported in either group. There was one myocardial ischemic event and one sudden death in the group receiving AVANDAMET plus insulin (N = 161). [See WARNINGS AND PRECAUTIONS]

The incidence of anemia was 2% for AVANDAMET in combination with insulin compared with 1% for insulin monotherapy.

Long-term Trial of Rosiglitazone as Monotherapy

A long-term, 4- to 6-year trial (ADOPT) compared the use of rosiglitazone (n = 1,456), glyburide (n = 1,441), and metformin (n = 1,454) as monotherapy in patients recently diagnosed with type 2 diabetes who were not previously treated with antidiabetic medication. Table 6 presents adverse reactions without regard to causality; rates are expressed per 100 patient-years (PY) exposure to account for the differences in exposure to trial medication across the 3 treatment groups.

In ADOPT, fractures were reported in a greater number of women treated with rosiglitazone (9.3%, 2.7/100 patient-years) compared with glyburide (3.5%, 1.3/100 patientyears) or metformin (5.1%, 1.5/100 patient-years). The majority of the fractures in the women who received rosiglitazone were reported in the upper arm, hand, and foot. [See WARNINGS AND PRECAUTIONS] The observed incidence of fractures for male patients was similar among the 3 treatment groups.

Table 6: On-therapy Adverse Events [≥5 Events/100 Patient-years (PY)] in any Treatment Group Reported in a 4- to 6-Year Clinical Trial of B osiglitazone as Monotherapy (ADOPT)

Preferred Term Rosiglitazone
N = 1,456
PY = 4,954		 Glyburide
N = 1,441
PY = 4,244		 Metformin
N = 1,454
PY = 4,906
Nasopharyngitis 6.3 6.9 6.6
Back pain 5.1 4.9 5.3
Arthralgia 5.0 4.8 4.2
Hypertension 4.4 6.0 6.1
Upper respiratory tract infection 4.3 5.0 4.7
Hypoglycemia 2.9 13.0 3.4
Diarrhea 2.5 3.2 6.8

Long-term Trial of Rosiglitazone as Combination Therapy (RECORD)

RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes) was a multicenter, randomized, open-label, non-inferiority trial in subjects with type 2 diabetes inadequately controlled on maximum doses of metformin or sulfonylurea (glyburide, gliclazide, or glimepiride) to compare the time to reach the combined cardiovascular endpoint of cardiovascular death or cardiovascular hospitalization between patients randomized to the addition of rosiglitazone versus metformin or sulfonylurea. The trial included patients who have failed metformin or sulfonylurea monotherapy; those who failed metformin (n = 2,222) were randomized to receive either add-on rosiglitazone (n = 1,117) or add-on sulfonylurea (n = 1,105), and those who failed sulfonylurea (n = 2,225) were randomized to receive either add-on rosiglitazone (n = 1,103) or add-on metformin (n = 1,122). Patients were treated to target HbA1c ≤ 7% throughout the trial.

The mean age of patients in this trial was 58 years, 52% were male, and the mean duration of follow-up was 5.5 years. Rosiglitazone demonstrated non-inferiority to active control for the primary endpoint of cardiovascular hospitalization or cardiovascular death (HR 0.99, 95% CI: 0.85-1.16). There were no significant differences between groups for secondary endpoints with the exception of congestive heart failure (see Table 7). The incidence of congestive heart failure was significantly greater among patients randomized to rosiglitazone.

Table 7:Cardiovascular (CV) Outcomes for the RECORD Trial

Primary Endpoint Rosiglitazone
N = 2,220		 Active Control
N = 2,227		 Hazard Ratio 95% CI
CV death or CV hospitalization 321 323 0.99 0.85-1.16
Secondary Endpoint
All-cause death 136 157 0.86 0.68-1.08
CV death 60 71 0.84 0.59-1.18
Myocardial infarction 64 56 1.14 0.80-1.63
Stroke 46 63 0.72 0.49-1.06
CV death, myocardial infarction, or stroke 154 165 0.93 0.74-1.15
Heart failure 61 29 2.10 1.35-3.27

There was an increased incidence of bone fracture for subjects randomized to rosiglitazone in addition to metformin or sulfonylurea compared with those randomized to metformin plus sulfonylurea (8.3% versus 5.3%) [see WARNINGS AND PRECAUTIONS]. The majority of fractures were reported in the upper limbs and distal lower limbs. The risk of fracture appeared to be higher in females relative to control (11.5% versus 6.3%), than in males relative to control (5.3% versus 4.3%). Additional data are necessary to determine whether there is an increased risk of fracture in males after a longer period of follow-up.

Laboratory Abnormalities

Hematologic

Decreases in mean hemoglobin and hematocrit occurred in a dose-related fashion in adult patients treated with rosiglitazone (mean decreases in individual trials as much as 1.0 gram/dL hemoglobin and as much as 3.3% hematocrit). The changes occurred primarily during the first 3 months following initiation of rosiglitazone therapy or following an increase in rosiglitazone dose. The time course and magnitude of decreases were similar in patients treated with a combination of rosiglitazone and other hypoglycemic agents or monotherapy with rosiglitazone. Pre-treatment levels of hemoglobin and hematocrit were lower in patients in  metformin combination trials and may have contributed to the higher reporting rate of anemia. In a single trial in pediatric patients, decreases in hemoglobin and hematocrit (mean decreases of 0.29 g/dL and 0.95%, respectively) were reported with rosiglitazone. White blood cell counts also decreased slightly in adult patients treated with rosiglitazone. Decreases in hematologic parameters may be related to increased plasma volume observed with rosiglitazone treatment.

In controlled clinical trials of metformin of 29 weeks' duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such a decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation.

Lipids

Changes in serum lipids have been observed following treatment with rosiglitazone in adults [see CLINICAL PHARMACOLOGY].

Serum Transaminase Levels

In pre-approval clinical trials in 4,598 patients treated with rosiglitazone encompassing approximately 3,600 patient-years of exposure, and in a longterm 4- to 6-year trial in 1,456 patients treated with rosiglitazone (4,954 patient-years exposure), there was no evidence of drug-induced hepatotoxicity.

In pre-approval controlled trials, 0.2% of patients treated with rosiglitazone had reversible elevations in ALT >3X the upper limit of normal compared with 0.2% on placebo and 0.5% on active comparators. The ALT elevations in patients treated with rosiglitazone were reversible. Hyperbilirubinemia was found in 0.3% of patients treated with rosiglitazone compared with 0.9% treated with placebo and 1% in patients treated with active comparators. In pre-approval clinical trials, there were no cases of idiosyncratic drug reactions leading to hepatic failure. [See WARNINGS AND PRECAUTIONS]

In the 4- to 6-year ADOPT trial, patients treated with rosiglitazone (4,954 patient-years exposure), glyburide (4,244 patient-years exposure), or metformin (4,906 patient-years exposure) as monotherapy, had the same rate of ALT increase to >3X upper limit of normal (0.3 per 100 patient-years exposure).

In the RECORD trial, patients randomized to rosiglitazone in addition to metformin or sulfonylurea (10,849 patient-years exposure) and to metformin plus sulfonylurea (10,209 patientyears exposure) had a rate of ALT increase to >3X upper limit of normal of approximately 0.2 and 0.3 per 100 patient-years exposure, respectively.

Postmarketing Experience

In addition to adverse reactions reported from clinical trials, the events described below have been identified during post-approval use of AVANDAMET or its individual components. Because these events are reported voluntarily from a population of unknown size, it is not possible to reliably estimate their frequency or to always establish a causal relationship to drug exposure.

In patients receiving thiazolidinedione therapy, serious adverse events with or without a fatal outcome, potentially related to volume expansion (e.g., congestive heart failure, pulmonary edema, and pleural effusions) have been reported [see BOXED WARNING, WARNINGS AND PRECAUTIONS].

There are postmarketing reports with rosiglitazone of hepatitis, hepatic enzyme elevations to 3 or more times the upper limit of normal, and hepatic failure with and without fatal outcome, although causality has not been established. There are postmarketing reports with rosiglitazone of rash, pruritus, urticaria, angioedema, anaphylactic reaction, Stevens-Johnson syndrome [see CONTRAINDICATIONS], and new onset or worsening diabetic macular edema with decreased visual acuity [see WARNINGS AND PRECAUTIONS]. (See also GLUCOPHAGE® prescribing information.)

Read the entire FDA prescribing information for Avandamet (Rosiglitazone Maleate and Metformin HCl)

&Copy; Avandamet Patient Information is supplied by Cerner Multum, Inc. and Avandamet Consumer information is supplied by First Databank, Inc., used under license and subject to their respective copyrights.