Special Warning : אזהרת שימוש

5 WARNINGS AND PRECAUTIONS

5.1 All-Cause Mortality
An increase in all-cause mortality has been observed in a meta-analysis of Phase 3 and 4 clinical trials in TYGACIL-treated patients versus comparator-treated patients. In all 13 Phase 3 and 4 trials that included a comparator, death occurred in 4.0% (150/3788) of patients receiving TYGACIL 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, the adjusted risk difference of all-cause mortality was 0.6% (95% CI 0.1, 1.2) between TYGACIL and comparator-treated patients. An analysis of mortality in all trials conducted for approved indications (cSSSI, cIAI, and CABP), including post-market trials 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).

The cause of this mortality difference has not been established. Generally, deaths were the result of worsening infection, complications of infection or underlying co-morbidities. TYGACIL should be reserved for use in situations when alternative treatments are not suitable [see Boxed Warning Indications and Usage (1.4), Warnings and Precautions (5.2) and Adverse Reactions (6.1)].

5.2 Mortality Imbalance and Lower Cure Rates in Hospital-Acquired Pneumonia 
A trial of patients with hospital acquired, including ventilator-associated, pneumonia failed to demonstrate the efficacy of TYGACIL. In this trial, patients were randomized to receive TYGACIL (100 mg initially, then 50 mg every 12 hours) or a comparator. In addition, patients were allowed to receive specified adjunctive therapies. The sub-group of patients with ventilator-associated pneumonia who received TYGACIL had lower cure rates (47.9% versus 70.1% for the clinically evaluable population).

In this trial, greater mortality was seen in patients with ventilator-associated pneumonia who received TYGACIL (25/131 [19.1%] versus 15/122 [12.3%] in comparator-treated patients) [see Adverse Reactions (6.1)]. Particularly high mortality was seen among TYGACIL-treated patients with ventilator-associated pneumonia and bacteremia at baseline (9/18 [50.0%] versus 1/13 [7.7%] in comparator-treated patients).

5.3 Anaphylactic Reactions

Anaphylactic reactions have been reported with nearly all antibacterial agents, including TYGACIL, and may be life-threatening. TYGACIL is structurally similar to tetracycline-class antibacterial drugs and should be avoided in patients with known hypersensitivity to tetracycline-class antibacterial drugs.

5.4 Hepatic Adverse Effects
Increases in total bilirubin concentration, prothrombin time and transaminases have been seen in patients treated with tigecycline. Isolated cases of significant hepatic dysfunction and hepatic failure have been reported in patients being treated with tigecycline. Some of these patients were receiving multiple concomitant medications. Patients who develop abnormal liver function tests during tigecycline therapy should be monitored for evidence of worsening hepatic function and evaluated for risk/benefit of continuing tigecycline therapy. Hepatic dysfunction may occur after the drug has been discontinued.

5.5 Pancreatitis
Acute pancreatitis, including fatal cases, has occurred in association with tigecycline treatment. The diagnosis of acute pancreatitis should be considered in patients taking tigecycline who develop clinical symptoms, signs, or laboratory abnormalities suggestive of acute pancreatitis. Cases have been reported in patients without known risk factors for pancreatitis. Patients usually improve after tigecycline discontinuation. Consideration should be given to the cessation of the treatment with tigecycline in cases suspected of having developed pancreatitis [see Adverse Reactions (6.2)].

5.6 Monitoring of Blood Coagulation Parameters

Hypofibrinogenemia has been reported in patients treated with TYGACIL [see Adverse Reactions (6.2)].
Obtain baseline blood coagulation parameters, including fibrinogen, and continue to monitor regularly during treatment with TYGACIL.


5.7 Tooth Discoloration and Enamel Hypoplasia
The use of TYGACIL during tooth development (last half of pregnancy, infancy, and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown). This adverse reaction is more common during long-term use of tetracyclines, but it has been observed following repeated short- term courses. Enamel hypoplasia has also been reported. Advise the patient of the potential risk to the fetus if TYGACIL is used during the second or third trimester of pregnancy [see Use in Specific Populations (8.1, 8.4)].

5.8 Inhibition of Bone Growth

The use of TYGACIL during the second and third trimester of pregnancy, infancy and childhood up to the age of 8 years may cause reversible inhibition of bone growth. All tetracyclines form a stable calcium complex in any bone-forming tissue. A decrease in fibula growth rate has been observed in premature infants given oral tetracycline in doses of 25 mg/kg every 6 hours. This reaction was shown to be reversible when the tetracycline was discontinued. Advise the patient of the potential risk to the fetus if TYGACIL is used during the second or third trimester of pregnancy [see Use in Specific Populations (8.1, 8.4)].


5.9 Clostridioides difficile Associated Diarrhea
Clostridioides difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including TYGACIL, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.


If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial drugtreatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.


    5.10 Sepsis/Septic Shock in Patients with Intestinal Perforation
Monotherapy with tigecycline should be avoided in patients with complicated intra-abdominal infections (cIAI) secondary to clinically apparent intestinal perforation. In cIAI studies (n=1642), 6 patients treated with TYGACIL and 2 patients treated with imipenem/cilastatin presented with intestinal perforations and developed sepsis/septic shock. The 6 patients treated with TYGACIL had higher APACHE II scores (median = 13) versus the 2 patients treated with imipenem/cilastatin (APACHE II scores = 4 and 6). Due to differences in baseline APACHE II scores between treatment groups and small overall numbers, the relationship of this outcome to treatment cannot be established.

5.11 Tetracycline-Class Adverse Effects
TYGACIL 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 TYGACIL 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.

5.13 Excipient information
TYGACIL contains less than 1 mmol sodium (23 mg) per 5 ml of solution. Patients on low sodium diets can be informed that this medicinal product is essentially ‘sodium free’ 
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 TYGACIL. TYGACIL 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
Body System                                         TYGACIL             Comparatorsa Adverse Reactions                                  (N=2514)            (N=2307) Body as a Whole
Abdominal pain                                     6                   4 Abscess                                            2                   2 Asthenia                                           3                   2 Table 1. Incidence (%) of Adverse Reactions Through Test of Cure Reported in ≥ 2% of Patients Treated in Clinical Studies
Body System                                               TYGACIL                Comparatorsa Adverse Reactions                                       (N=2514)               (N=2307) 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                                    3                      3 Increased
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 b
SGPT Increased                                          5                      5 Respiratory System
Pneumonia                                               2                      2 Nervous System
Dizziness                                               3                      3 Skin and Appendages
Rash                                                    3                      4 a
Vancomycin/Aztreonam, Imipenem/Cilastatin, Levofloxacin, Linezolid.
b
LFT abnormalities in TYGACIL-treated patients were reported more frequently in the post therapy period than those in comparator-treated patients, which occurred more often on therapy.

In all 13 Phase 3 and 4 trials that included a comparator, death occurred in 4.0% (150/3788) of patients receiving TYGACIL 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 TYGACIL 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
TYGACIL                 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) a
VAP              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)** 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 TYGACIL 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).

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 TYGACIL (7%) versus comparators (6%). Serious adverse reactions of sepsis/septic shock were more frequently reported for subjects treated with TYGACIL (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 TYGACIL and comparators were either mild or moderate in severity. In patients treated with TYGACIL, 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 TYGACIL and 9% for vancomycin/aztreonam; vomiting incidence was 20% for TYGACIL and 4% for vancomycin/aztreonam. In patients treated for complicated intra-abdominal infections (cIAI), nausea incidence was 25% for TYGACIL and 21% for imipenem/cilastatin; vomiting incidence was 20% for TYGACIL and 15% for imipenem/cilastatin. In patients treated for community-acquired bacterial pneumonia (CABP), nausea incidence was 24% for TYGACIL and 8% for levofloxacin; vomiting incidence was 16% for TYGACIL and 6% for levofloxacin.

Discontinuation from TYGACIL 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 TYGACIL 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

6.2 Post-Marketing Experience
The following adverse reactions have been identified during post-approval use of TYGACIL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.
•       anaphylactic reactions
•       acute pancreatitis
•       hepatic cholestasis, and jaundice
•       severe skin reactions, including Stevens-Johnson Syndrome
•       symptomatic hypoglycemia in patients with and without diabetes mellitus
•       hypofibrinogenemia [see Warnings and Precautions (5.6)] 
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il/

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