Gemcitabine Indications, Dose, Adverse Effects, And Mechanism of Action For Cancer

Gemcitabine Indications, Dose, Adverse Effects, And Mechanism of Action For Cancer
Gemcitabine Indications, Dose, Adverse Effects, And Mechanism of Action For Cancer

A. Drug Name

GEMCITABINE

COMMON TRADE NAME(S): Gemzar® (multiple brands available).

B. Mechanism of Action and Pharmacokinetics

Gemcitabine is a deoxycytidine analogue, a pyrimidine antimetabolite related to cytarabine. Gemcitabine exhibits cell phase specificity, primarily killing cells undergoing DNA synthesis (S-phase) and also blocking the progression of cells through the G1/S-phase boundary. Gemcitabine is a pro-drug and is metabolized intracellularly to the active diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides. The cytotoxic effects of gemcitabine are exerted through dFdCDP inhibition of ribonucleotide reductase and incorporation of dFdCTP into DNA, resulting in inhibition of DNA synthesis and induction of apoptosis.

C. Indications and Status

Health Canada Approvals:
  • Locally advanced (unresectable) or metastatic adenocarcinoma of the pancreas 
  • Locally advanced or metastatic non-small cell lung cancer (NSCLC) as a single agent or in combination with cisplatin 
  • In combination with cisplatin for locally advanced or metastatic transitional cell carcinoma (TCC) of the bladder 
  • In combination with paclitaxel for unresectable, locally recurrent or metastatic breast cancer, who have good performance status and have relapsed following adjuvant anthracycline-based chemotherapy
Other Uses
  • Breast cancer 
  • Gastrointestinal cancer (advanced biliary tract cancer, adjuvant treatment of pancreatic cancer) 
  • Genitourinary cancers (adrenal, testicular cancer, renal cell) 
  • Gynecological cancers (ovarian, cervical) 
  • Germ cell cancers 
  • Sarcoma (leiomyosarcoma of the uterus, soft tissue sarcoma) 
  • Head and neck cancer 
  • Mesothelioma 
  • Non-Hodgkin’s and Hodgkin’s lymphoma 
  • Unknown primary cancer
D. Adverse Effects

Emetogenic Potential: Low
Extravasation Potential: None

The following table contains adverse effects with ≥ 5% frequency, in patients treated with gemcitabine 800-1250 mg/m2 (single agent) weekly, as a 30 minute infusion for various malignancies.


ORGAN SITE
SIDE EFFECT* (%)
ONSET**
Cardiovascular

Arrhythmia (rare)
E


Arterial thromboembolism (rare)
E


Heart failure (rare)
E


Hypertension (<2%)
E
Dermatological

Alopecia (14%)
E


Rash (25%) (may be severe)
E
Gastrointestinal

Constipation (8%)
E


Diarrhea (12%)
E


Mucositis (8%)
E


Nausea, vomiting (64%) (severe 18%)
I  E
General

Edema (20%)
E


Fatigue (40%) (in combination with paclitaxel)
I


Flu-like symptoms (37%)
I


Other (radiosensitizer)
E  D
Hematological

Hemolytic uremic syndrome (<1%)
E









Myelosuppression ± infection, bleeding (25%) (severe)
E
Hepatobiliary

↑ LFTs (68%) (10% severe)

E
Hypersensitivity

Hypersensitivity (rare)
I
Infection

Infection (9%) (severe 1%)
E
Injection site

Injection site reaction (4%)
I
Musculoskeletal

Musculoskeletal pain (16%)
I
Nervous System

Peripheral neuropathy (3%)
E


PRES (rare)
E  D







Somnolence (9%)
E















Renal
Creatinine increased (7%)
E

Proteinuria (36%)
E
Respiratory
Adult respiratory distress syndrome (ARDS) (rare)
E

Dyspnea (8%)
I

Pneumonitis (rare)

E
Vascular
Capillary leak syndrome (rare)
E  D

Gangrene (rare)

E

Vasculitis (rare)
E


* "Incidence" may refer to an absolute value or the higher value from a reported range.

"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,

isolated data or anecdotal reports.

Dose-limiting side effects are underlined.
** I = immediate (onset in hours to days)     E  = early (days to weeks)

D = delayed (weeks to months)     L = late (months to years)


The most common side effects for gemcitabine include ↑ LFTs, nausea/vomiting, fatigue, flu-like symptoms, proteinuria, myelosuppression ± infection/bleeding, rash, edema, musculoskeletal pain and alopecia.

The main dose-limiting toxicity with gemcitabine is myelosuppression (non-cumulative). In combinations with cisplatin, increased thrombocytopenia, GI and neurotoxicity have been observed. In combination with paclitaxel, increased grade 4 neutropenia, myalgia and neurotoxicity were reported.

Transient rashes of macular, erythematous, and pruritic types involving the trunk and the extremities were reported. Topical corticosteroids may provide symptomatic relief.

Edema was frequently reported but usually mild to moderate, reversible after stopping gemcitabine treatment and rarely resulted in discontinuation. The mechanism of edema is unknown but was not associated with any evidence of cardiac, hepatic or renal failure.

Flu-like symptoms are common and consist of low-grade fever, headache, fatigue, malaise, myalgia, arthralgia, cough and rhinitis, starting the evening after gemcitabine infusion and may last up to several days. These can be relieved by acetaminophen>
Pulmonary edema, interstitial pneumonitis, or adult respiratory distress syndrome (ARDS) has been reported rarely. The mechanism of this toxicity is unknown.

Capillary leak syndrome and posterior reversible encephalopathy syndrome (PRES) have been reported rarely in single agent or combination therapy and may be severe. The mechanism relates to gemcitabine-induced vascular injury. If these effects develop, gemcitabine should be discontinued and supportive therapy instituted.

Rare occurrences of hemolytic uremic syndrome, including fatal cases, were reported. Renal failure associated with this syndrome may not be reversible even with discontinuation of therapy and dialysis may be required. Patients with pre-existing renal dysfunction should be followed closely while being treated with gemcitabine.

Patients receiving concurrent radiation while receiving full dose gemcitabine should be closely monitored for reactions. Potentially life-threatening esophagitis and pneumonitis, particularly in patients receiving large volumes of radiotherapy, have been observed. Radiation injury has been observed on targeted tissues (e.g. esophagitis, colitis, and pneumonitis) with both concurrent and non-concurrent gemcitabine use.

E. Dosing

Adults:

 Pancreatic cancer: 

Cycle 1: 1000 mg/m2 weekly for 7 weeks with 1 week rest

Cycle 2 on: 1000 mg/m2 weekly for 3 weeks with 1 week rest (Q4W)

NSCLC:

Q 4 w: 1000 mg/m2 weekly for 3 weeks ± cisplatin 100 mg/m2 after infusion Day 1 ONLY

Q 3 w: 1250 mg/m2 weekly for 2 weeks ± cisplatin 100 mg/m2 after infusion Day 1 ONLY


TCC of the Bladder:

Q 4 w: 1000 mg/m2 weekly for 3 weeks, with cisplatin 70mg/m2 day 1 ONLY


Breast cancer:

Q 3 w: 1250 mg/m2 weekly for 2 weeks, with paclitaxel 175mg/m2 on day 1 ONLY


Dosage with Toxicity:
Dose on Day 1 of Cycle:

Non-hematologic

Hematologic
% Full Dose*




Grade 3
or
Febrile neutropenia,
75%


thrombocytopenic



bleeding

Grade 4
Consider discontinuing,
or
or  ↓ to  75%
Day 8/15 holds on > 1

cycle



Pneumonitis
Discontinue
Hemolytic Uremic

Syndrome (HUS)

Stevens-Johnson

syndrome (SJS)

Toxic epidermal

necrolysis (TEN)

Capillary Leak

Syndrome (CLS)

Posterior

reversible

encephalopathy

syndrome (PRES)


* Do not start new cycle until ANC ≥ 1500 x 106/L, platelets ≥ 100,000 x 106/L and non-hematologic toxicity ≤ grade 2.

Single agent or combinations other than paclitaxel in breast cancer: 

Dose on Day 8 or 15 of Cycle:


Non-

Hematologic
% Full Dose


hematologic








ANC

Platelets











(x 106/L)

(x 106/L)



≤ grade 2
and
> 1000
and
> 100,000
100%










≤ grade 2
and
500-1000

50,000-
Consider Omit,





or
100,000
or  ↓ to 75%









Grade 3 or 4
or
< 500
or
< 50,000Omit; ↓ to 75% at restart







(if applicable) for non-







hematologic toxicity










Pneumonitis

-

-
Discontinue


HUS







SJS







TEN







CLS or PRES
























In Breast Cancer, in combination with paclitaxel:

Dose on Day 8 of Cycle:

Non-


Hematologic
% Full Dose
hematologic













ANC

Platelets



(x 106/L)

(x 106/L)

≤ grade 2
and
≥ 1200
and
> 75,000
100%






≤ grade 2
and
1000 -

50000 -
75%


1199
or
75000








and
700 - 999
and
≥ 50,000
↓ to  50%
≤ grade 2











Grade 3 or 4
or
< 700
or
< 50,000
Omit; ↓ to 75% at





restart (if applicable) for





non-hematologic toxicity






Pneumonitis

-

-
Discontinue
HUS





SJS







Dosage with Hepatic Impairment:

Gemcitabine should be used with caution in patients with hepatic impairment (cirrhosis, hepatitis, alcoholism, metastases, etc.); initial dose reduction should be considered if the patient is treated, especially in hyperbilirubinemia.

Suggested:


Bilirubin (micromol/L)
Starting dose






> 27
800 mg/m2; escalated if tolerated



Dosage with Renal Impairment:

Gemcitabine should be used with caution in patients with renal insufficiency; clinical trials with cisplatin mandated CrCl ≥ 60mL/min. For patients with pre-existing renal insufficiency, the close monitoring for occurrence of hemolytic uremic syndrome is required. No specific recommendations found.

Dosage in the elderly:

Clearance is lower in the elderly but no dose adjustment necessary.

Dosage based on gender:

Clearance is lower in women but no dose adjustment necessary.

Children:

Safety and effectiveness in children have not been established.


F. Administration Guidelines
  • May dilute reconstituted drug in normal saline for IV infusion, resulting in a minimum final concentration of at least 0.1 mg/mL. 
  • Gemcitabine should be given by IV infusion over 30 minutes. 
  • Avoid using as a prolonged infusion (more than 60 minutes) or more frequently than weekly, since this can increase toxicity. 
G. Special Precautions

Contraindications:
  • patients who have a hypersensitivity to this drug or any of its components 
Other Warnings/Precautions:
  • extreme caution in patients with compromised bone marrow 
  • patients with hepatic impairment (including concurrent liver metastases or a previous history of 
  • hepatitis, alcoholism or liver cirrhosis) 
  • patients with renal impairment 
  • patients receiving concurrent radiation while receiving full dose gemcitabine should be closely monitored for reactions. Potentially life-threatening esophagitis and pneumonitis, particularly in patients receiving large volumes of radiotherapy have been observed. 
Pregnancy and Lactation:
  • Clastogenicity: Yes 
  • Mutagenicity: Yes 
  • Embryotoxicity: Yes 
  • Fetotoxicity: Yes 
  • Gemcitabine is not recommended for use in pregnancy. Adequate contraception should be used by both sexes during treatment, and for at least 6 months (general recommendation) after the last dose. 
  • Excretion into breast milk: Unknown 
  • Breastfeeding is not recommended. 
  • Fertility effects: Probable 
  • Male fertility may be affected. 

References 

Gemcitabine Product Monograph. Teva Canada Limited, June 9, 2014.
Aapro MS, Martin C, Hatty S. Review paper: gemcitabine - a safety review. Anti-Cancer Drugs 1998;9:191-201.
Floyd J, Mirza I, Sachs B, et al. Hepatotoxicity of chemotherapy. Semin Oncol 2006;33(1):50-67.
Noble S, Goa K. Gemcitabine: a review of its pharmacology and clinical potential in non-small cell lung cancer and pancreatic cancer. Drugs 1997;54(3):447-72.
Saif MW. Interaction between Gemcitabine and Warfarin Causing Gastrointestinal Bleeding in a Patient with Pancreatic Cancer. J Appl Res 2005;5(3):434-37.

February 2018 edited distribution, adverse effects, dosage with hepatic impairment, administration, precautions, and monitoring sections
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