Tigecycline (Page 3 of 8)

5.11 Tetracycline-Class Adverse Effects

Tigecycline is structurally similar to tetracycline-class antibacterial drugs and may have similar adverse effects. Such effects may include: photosensitivity, pseudotumor cerebri, and anti-anabolic action (which has led to increased BUN, azotemia, acidosis, and hyperphosphatemia).

5.12 Development of Drug-Resistant Bacteria

Prescribing tigecycline in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

6 ADVERSE REACTIONS

The following serious adverse reactions are described elsewhere in the labeling:

• All-Cause Mortality [see Boxed Warning and Warnings and Precautions (5.1)]
• Mortality Imbalance and Lower Cure Rates in Hospital-Acquired Pneumonia [see Warnings and Precautions (5.2)]
• Anaphylaxis [Warning and Precautions (5.3)]
• Hepatic Adverse Effects [Warnings and Precautions (5.4)]
• Pancreatitis [Warnings and Precautions (5.5)]

6.1 Clinical Trials 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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In clinical trials, 2514 patients were treated with tigecycline. Tigecycline was discontinued due to adverse reactions in 7% of patients compared to 6% for all comparators. Table 1 shows the incidence of adverse reactions through test of cure reported in ≥2% of patients in these trials.

Table 1. Incidence (%) of Adverse Reactions Through Test of Cure Reported in ≥ 2% of Patients Treated in Clinical Studies

a Vancomycin/Aztreonam, Imipenem/Cilastatin, Levofloxacin, Linezolid.
b LFT abnormalities in tigecycline-treated patients were reported more frequently in the post therapy period than those in comparator-treated patients, which occurred more often on therapy.
Body System	Tigecycline	Comparatorsa
Adverse Reactions	(N=2514)	(N=2307)
Body as a Whole
Abdominal pain	6	4
Abscess	2	2
Asthenia	3	2
Headache	6	7
Infection	7	5
Cardiovascular System
Phlebitis	3	4
Digestive System
Diarrhea	12	11
Dyspepsia	2	2
Nausea	26	13
Vomiting	18	9
Hemic and Lymphatic System
Anemia	5	6
Metabolic and Nutritional
Alkaline Phosphatase Increased	3	3
Amylase Increased	3	2
Bilirubinemia	2	1
BUN Increased	3	1
Healing Abnormal	3	2
Hyponatremia	2	1
Hypoproteinemia	5	3
SGOT Increasedb	4	5
SGPT Increasedb	5	5
Respiratory System
Pneumonia	2	2
Nervous System
Dizziness	3	3
Skin and Appendages
Rash	3	4

In all 13 Phase 3 and 4 trials that included a comparator, death occurred in 4.0% (150/3788) of patients receiving tigecycline and 3.0% (110/3646) of patients receiving comparator drugs. In a pooled analysis of these trials, based on a random effects model by trial weight, an adjusted risk difference of all-cause mortality was 0.6% (95% CI 0.1, 1.2) between tigecycline and comparator-treated patients (see Table 2). The cause of the imbalance has not been established. Generally, deaths were the result of worsening infection, complications of infection or underlying co-morbidities.

Table 2. Patients with Outcome of Death by Infection Type

CAP = Community-acquired pneumonia; cIAI = Complicated intra-abdominal infections; cSSSI = Complicated skin and skin structure infections; HAP = Hospital-acquired pneumonia; VAP = Ventilator-associated pneumonia; RP = Resistant pathogens; DFI = Diabetic foot infections.
* The difference between the percentage of patients who died in tigecycline and comparator treatment groups. The 95% CI for each infection type was calculated using the normal approximation method without continuity correction.
** Overall adjusted (random effects model by trial weight) risk difference estimate and 95% CI.
a These are subgroups of the HAP population.
Note: The studies include 300, 305, 900 (cSSSI), 301, 306, 315, 316, 400 (cIAI), 308 and 313 (CAP), 311 (HAP), 307 [Resistant gram-positive pathogen study in patients with MRSA or Vancomycin-Resistant Enterococcus (VRE)], and 319 (DFI with and without osteomyelitis).
	Tigecycline		Comparator		Risk Difference*
Infection Type	n/N	%	n/N	%	% (95% CI)
cSSSI	12/834	1.4	6/813	0.7	0.7 (-0.3, 1.7)
cIAI	42/1382	3.0	31/1393	2.2	0.8 (-0.4, 2.0)
CAP	12/424	2.8	11/422	2.6	0.2 (-2.0, 2.4)
HAP	66/467	14.1	57/467	12.2	1.9 (-2.4, 6.3)
Non-VAPa	41/336	12.2	42/345	12.2	0.0 (-4.9, 4.9)
VAPa	25/131	19.1	15/122	12.3	6.8 (-2.1, 15.7)
RP	11/128	8.6	2/43	4.7	3.9 (-4.0, 11.9)
DFI	7/553	1.3	3/508	0.6	0.7 (-0.5, 1.8)
Overall Adjusted	150/3788	4.0	110/3646	3.0	0.6 (0.1, 1.2)**

An analysis of mortality in all trials conducted for approved indications — cSSSI, cIAI, and CABP, including post-market trials (one in cSSSI and two in cIAI) — showed an adjusted mortality rate of 2.5% (66/2640) for tigecycline and 1.8% (48/2628) for comparator, respectively. The adjusted risk difference for mortality stratified by trial weight was 0.6% (95% CI 0.0, 1.2).

In comparative clinical studies, infection-related serious adverse reactions were more frequently reported for subjects treated with tigecycline (7%) versus comparators (6%). Serious adverse reactions of sepsis/septic shock were more frequently reported for subjects treated with tigecycline (2%) versus comparators (1%). Due to baseline differences between treatment groups in this subset of patients, the relationship of this outcome to treatment cannot be established [see Warnings and Precautions (5.10)].

The most common adverse reactions were nausea and vomiting which generally occurred during the first 1 – 2 days of therapy. The majority of cases of nausea and vomiting associated with tigecycline and comparators were either mild or moderate in severity. In patients treated with tigecycline, nausea incidence was 26% (17% mild, 8% moderate, 1% severe) and vomiting incidence was 18% (11% mild, 6% moderate, 1% severe).

In patients treated for complicated skin and skin structure infections (cSSSI), nausea incidence was 35% for tigecycline and 9% for vancomycin/aztreonam; vomiting incidence was 20% for tigecycline and 4% for vancomycin/aztreonam. In patients treated for complicated intra-abdominal infections (cIAI), nausea incidence was 25% for tigecycline and 21% for imipenem/cilastatin; vomiting incidence was 20% for tigecycline and 15% for imipenem/cilastatin. In patients treated for community-acquired bacterial pneumonia (CABP), nausea incidence was 24% for tigecycline and 8% for levofloxacin; vomiting incidence was 16% for tigecycline and 6% for levofloxacin.

Discontinuation from tigecycline was most frequently associated with nausea (1%) and vomiting (1%). For comparators, discontinuation was most frequently associated with nausea (<1%).

The following adverse reactions were reported (<2%) in patients receiving tigecycline in clinical studies:

Body as a Whole: injection site inflammation, injection site pain, injection site reaction, septic shock, allergic reaction, chills, injection site edema, injection site phlebitis

Cardiovascular System: thrombophlebitis

Digestive System: anorexia, jaundice, abnormal stools

Metabolic/Nutritional System: increased creatinine, hypocalcemia, hypoglycemia

Special Senses: taste perversion

Hemic and Lymphatic System: prolonged activated partial thromboplastin time (aPTT), prolonged prothrombin time (PT), eosinophilia, increased international normalized ratio (INR), thrombocytopenia

Skin and Appendages: pruritus

Urogenital System: vaginal moniliasis, vaginitis, leukorrhea