What are alternatives to intravenous (IV) famotidine as a premedication for chemotherapy-induced infusion reactions such as paclitaxel? Are there any studies looking at oral famotidine as premedication?

Comment by InpharmD Researcher

While the evidence directly comparing intravenous (IV) famotidine to other H2 antagonists is scarce, IV ranitidine and cimetidine have been successfully used for taxane-induced infusion reactions, including paclitaxel. Paclitaxel’s label recommends using IV cimetidine (300 mg) or ranitidine (50 mg) 30 to 60 minutes before injection. One retrospective study found oral famotidine was non-inferior to IV ranitidine in preventing hypersensitivity reactions (HSR) caused by paclitaxel. However, the added value of H2 antagonists as part of the premedication regimen appears equivocal, as recent data suggest omission of H2 antagonists was not associated with increased incidence of paclitaxel-induced HSR.

Background

Per the 2017 European Society for Medical Oncology (ESMO) guidelines, concurrent use of histamine-1 (H1) and H2 antagonists is superior to the use of H1 (diphenhydramine) or H2 antagonists (ranitidine, cimetidine) alone in the management of infusion reactions (IRs). If such reactions are noted during the administration of medication, the guidelines recommend using diphenhydramine (1–2 mg/kg or 25–50 mg) given via slow intravenous (IV) injection in combination with ranitidine (50 mg diluted in 5% dextrose water to a total volume of 20 mL) over 5 minutes. Without premedication, paclitaxel is associated with 30% of IRs; thus, prophylaxis with one dose of IV dexamethasone plus diphenhydramine (50 mg IV) and an H2 receptor antagonist (ranitidine 50 mg or cimetidine 300 mg IV) 30 minutes prior to paclitaxel infusion deems necessary. [1]

A 2022 literature review describes premedication protocols to prevent hypersensitivity reactions (HSRs) to chemotherapy including taxanes. Premedications with H2 blockers (e.g., IV cimetidine 300 mg or ranitidine 50 mg) have been used in studies in addition to corticosteroids and H1 blockers (e.g., diphenhydramine 50 mg), resulting in a reduction in HSRs. However, in general, the added value of H2 blockers as part of the premedication protocols seems to be equivocal as a recent study (see Table 1) revealed a premedication regimen without ranitidine is non-inferior to the standard premedication regimen with ranitidine in preventing HSRs associated with paclitaxel chemotherapy. [2]

Hypersensitivity symptoms to taxanes typically develop within the first 10-15 minutes after infusion. In the vast majority of cases (95%), reactions will manifest during the first two infusions, although in rare cases reactions may appear with subsequent infusions as well. Delayed skin reaction may occur in some cases, presenting days after the initial exposure. The overall incidence of paclitaxel and docetaxel hypersensitivity is reported to range from 8% to 50%. The risk of hypersensitivity may be heightened in patients with a history of atopy, mild skin reactions during earlier treatments, the presence of respiratory dysfunction, overweight or obesity, and menopausal or postmenopausal status. [3]

The routine premedication with glucocorticoids was reported to be effective in reducing the incidence of hypersensitivity during paclitaxel or docetaxel therapy from 30% to 1-3%. Studies have reported success with the administration of dexamethasone 12 and 6 hours before infusion but lacked conclusive data to determine the most optimal administration regimen compared to a single administration given 30 minutes prior to the infusion. For docetaxel, dexamethasone 8 mg for 3 days starting the day before infusion has been found to reduce the incidence of grade 3 or 4 hypersensitivity reactions to about 2%. While the reviewers highlighted the need for routine premedication with glucocorticoids and H1 and H2 antagonists to reduce the risk of HSRs associated with taxanes, they did not prefer a specific H2 antagonist. Either IV famotidine 20 mg or ranitidine 50 mg was described in studies with desensitization protocols. [3]

A review article described a small crossover kinetic study from 1995 comparing IV famotidine 20 mg given 30 minutes preinfusion and IV cimetidine 300 mg given 30 minutes preinfusion. The study included 27 cancer patients with previous exposure to paclitaxel. Steady-state values of paclitaxel were not altered based on the pretreatment drug, suggesting the premedication regimen may be interchangeable between famotidine and cimetidine. The efficacy of either agent for reducing infusion reactions was not detailed, but the degree and incidence of severe neutropenia did not differ between the two premedication regimens. [4], [5]

References:

[1] Roselló S, Blasco I, García Fabregat L, Cervantes A, Jordan K; ESMO Guidelines Committee. Management of infusion reactions to systemic anticancer therapy: ESMO Clinical Practice Guidelines. Ann Oncol. 2018;29(Suppl 4):iv260. doi:10.1093/annonc/mdy158
[2] ​​ALMuhizi F, De Las Vecillas Sanchez L, Gilbert L, Copaescu AM, Isabwe GAC. Premedication Protocols to Prevent Hypersensitivity Reactions to Chemotherapy: a Literature Review [published online ahead of print, 2022 Mar 8]. Clin Rev Allergy Immunol. 2022;10.1007/s12016-022-08932-2. doi:10.1007/s12016-022-08932-2
[3] Boulanger J, Boursiquot JN, Cournoyer G, et al. Management of hypersensitivity to platinum- and taxane-based chemotherapy: cepo review and clinical recommendations. Curr Oncol. 2014;21(4):e630-e641. doi:10.3747/co.21.1966
[4] Generali J, Cada DJ. Famotidine: prevention of paclitaxel hypersensitivity reactions. Hosp Pharm. 2001;36(7):766-770.
[5] Slichenmyer WJ, Donehower RC, Chen TL, Bowling MK, McGuire WP, Rowinsky EK. Pretreatment H2 receptor antagonists that differ in P450 modulation activity: comparative effects on paclitaxel clearance rates and neutropenia. Cancer Chemother Pharmacol. 1995;36(3):227-232.
Relevant Prescribing Information

Hypersensitivity Reactions:
Patients with a history of severe hypersensitivity reactions to products containing Cremophor® EL (e.g., cyclosporin for injection concentrate and teniposide for injection concentrate) should not be treated with Paclitaxel Injection, USP. In order to avoid the occurrence of severe hypersensitivity reactions, all patients treated with paclitaxel should be premedicated with corticosteroids (such as dexamethasone), diphenhydramine and H2 antagonists (such as cimetidine or ranitidine). Minor symptoms such as flushing, skin reactions, dyspnea, hypotension, or tachycardia do not require interruption of therapy. However, severe reactions, such as hypotension requiring treatment, dyspnea requiring bronchodilators, angioedema, or generalized urticaria require immediate discontinuation of paclitaxel and aggressive symptomatic therapy. Patients who have developed severe hypersensitivity reactions should not be rechallenged with paclitaxel.

Dosage and Administration:
​​All patients should be premedicated prior to Paclitaxel Injection, USP administration in order to prevent severe hypersensitivity reactions. Such premedication may consist of dexamethasone 20 mg PO administered approximately 12 and 6 hours before Paclitaxel Injection USP, diphenhydramine (or its equivalent) 50 mg intravenous 30 to 60 minutes prior to Paclitaxel Injection USP, and cimetidine (300 mg) or ranitidine (50 mg) intravenous 30 to 60 minutes before Paclitaxel Injection, USP.

References:

Paclitaxel injection solution [prescribing information]. Actavis Pharma, Inc; 2017.

Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

What are alternatives, available in the US, to intravenous (IV) famotidine as a premedication for chemotherapy-induced infusion reactions such as paclitaxel? Are there any studies looking at oral famotidine as premedication?

Level of evidence

A - Multiple high-quality studies with consistent results  Read more→


Please see Tables 1-3 for your response.

 

The added value of H2 antagonists in premedication regimens during paclitaxel treatment

Design

Single-center, prospective, pre-post interventional, non-inferiority study

N= 366

Objective

To determine the added value of ranitidine in preventing clinically relevant hypersensitivity reactions (HSRs) by comparing the standard premedication regimen with ranitidine to an experimental premedication regimen without ranitidine

Study Groups

Ranitidine (n= 183)

Without ranitidine (n= 183)

Inclusion Criteria

Paclitaxel-naive patients; aged ≥ 18 years; within the outpatient department; planned to receive their first cycle of paclitaxel for systemic cancer treatment

Exclusion Criteria

Not explicitly specified

Methods

Eligible patients received paclitaxel as part of a combination regimen or given as monotherapy in either a weekly or 3-weekly cycle. Patients in the pre-intervention group received the standard premedication regimen consisting of dexamethasone 10 mg intravenously [IV]), clemastine (2 mg IV), and ranitidine (50 mg IV). Patients in the post-interventional group received the experimental premedication regimen without the H2 antagonist ranitidine. Patients in both groups were followed for a minimum of two cycles and a maximum of six cycles of paclitaxel infusions if no HSR would occur or until the occurrence of the first HSR within the first six cycles. A non-inferiority margin of +6% was chosen in this study in order to set feasible goals for the number of patients within a specific time frame. 

Duration

Premedication period:

With ranitidine: October 2018 through April 19, 2019

Without ranitidine: April 19, 2019 through December 2019

Outcome Measures

Primary: incidence of HSRs grade ≥3 during paclitaxel treatment

Secondary: severity of paclitaxel-induced HSR; the number of paclitaxel dosages until the first HSR occurrence

Baseline Characteristics

  

Ranitidine (n= 183)

Without ranitidine (n= 183)

    

Age (IQR), years

 61 (51 to 70) 61 (51 to 70)    

Female

115 (62.8%) 106 (57.9%)    

Tumor type*:

Uterine cervical

Lung

Breast

Ovarian

Oesophageal

Endometrial 

 

20 (10.9%)

3 (1.6%)

60 (32.8%)

10 (5.5%)

78 (42.6%)

5 (2.7%)

 


9 (4.9%)

29 (15.8%)

59 (32.2%)

2 (1.1%)

76 (41.5%)

4 (2.2%)

 		    

Allergies

Medication 

Food

 

37 (20.2%)

3 (1.6%)

 

31 (16.9%)

3 (1.6%)

    

Co-medication with effect on allergy symptoms**

Corticosteroids

Beta-blockers

Immunomodulatory agents

Anti-histamines

 

 

18 (9.8%)

20 (10.9%)

2 (1.1%)

9 (4.9%)

 

 

18 (9.8%)

26 (14.2%)

0

9 (4.9%)

    

IQR, Interquartile Range

*p< 0.001

**Excluding chemotherapy-related medication

Results

Endpoint

Ranitidine (n= 183)

Without ranitidine (n= 183)

Absolute risk difference (90% confidence interval)

p-value

HSR incidence

Any grade¶

Grade ≥3

 

37 (20%)

8 (4.4%)

 

22 (12%)

3 (1.6%)

 

−8.2% (−15.0 to −1.4)

−2.7% (−6.2 to 0.1)

 

0.046

-

The severity of HSRs, the number of paclitaxel dosages, and the time to first HSR occurrence did not differ between the groups.

Non-inferiority was shown.

Adverse Events

N/A

Study Author Conclusions

As the upper boundary of the 90% CI does not exceed the predefined non-inferiority margin of +6%, it can be concluded that a premedication regimen without ranitidine is non-inferior to a premedication regimen with ranitidine.

InpharmD Researcher Critique

In addition to limitations based on its non-randomized design, the tumor type was significantly different between the two groups. Moreover, the HSR incidence of ranitidine premedication compared to other H2 antagonist premedications remain unknown.



References:

Cox JM, van Doorn L, Malmberg R, et al. The added value of H2 antagonists in premedication regimens during paclitaxel treatment. Br J Cancer. 2021;124(10):1647-1652. doi:10.1038/s41416-021-01313-0

 

Histamine-2 (H2) antagonists can be safely removed from standard paclitaxel premedication regimens

Design

Prospective, multi-center, cohort study

N= 1,043

Objective

To investigate the rates of hypersensitivity reactions (HSRs) in patients receiving paclitaxel chemotherapy, with and without a histamine-2 (H2) antagonists

Study Groups

H2 antagonist (N= 638)

None (n= 405)

Inclusion Criteria

Patients commencing treatment with paclitaxel at included hospitals 

Exclusion Criteria

Patients treated with paclitaxel-albumin (nab-paclitaxel) and those who received paclitaxel as part of a clinical trial, including as a phase I or II investigational medicinal product (IMP)

Methods

Participating centers in the UK utilized an Excel-based data collection tool to gather relevant data, including demographic information, disease diagnosis, treatment regimens (line of therapy, dosing, concurrent chemotherapy), details of premedication regimens, and any HSRs experienced by patients. Any HSRs identified were categorized and graded in accordance with common terminology criteria for adverse events (CTCAE) v5. Logistic multivariable regression was utilized to investigate the outcome of any reported HSR and identify the associations with H2 antagonist treatment, adjusting for confounding variables.

Duration

Not specified 

Outcome Measures

Incidence of HSR

Baseline Characteristics

  

H2 antagonist (N = 638)

None (n= 405) 

 p-value

Age, years

< 60 years 

≥ 60 years

 

275 (43%)

363 (57%)

 

144 (36%)

261 (64%)

 0.015

Female

598 (94%) 334 (82%) < 0.001

Diagnosis 

Breast

Gynecological

Lung

Upper gastrointestine 

Other

 

247 (39%)

193 (30%)

29 (4.5%)

23 (3.6%)

146 (23%)

 

143 (35%)

147 (36%)

53 (13%)

37 (9.1%)

25 (6.2%)

 < 0.001

Chemotherapy combination

 108 (17%) 1 (0.2%) < 0.001

Dexamethasone dose

< 8 mg

8–16 mg

> 16 mg

None

 

94 (15%)

302 (47%)

241 (38%)

1 (0.2%)

 

15 (3.7%)

255 (63%)

129 (32%)

6 (1.5%)

 < 0.001

Chlorphenamine IV

636 (100%)

 399 (99%) 0.062

Dose per meter squared

< 100 mg/m2

≥ 100 mg/m2

 

347 (54%)

291 (46%)

 

244 (60%)

161 (40%)

 0.063

Results

Endpoint

H2 antagonist (N = 638)

None (n= 416)

p-value

Reaction at any point

 70 (11%) 41 (9.9%) 0.5

Highest grade reaction

0

1

2

3

 

549 (89%)

5 (0.8%)

57 (9.2%)

6 (1.0%)

 

375 (90%)

1 (0.2%)

36 (8.7%)

4 (1.0%)

 0.7

Dose number when first reaction occurred

1

2

3

4

5

6

7

9

 

29 (41%)

32 (46%)

6 (8.6%)

1 (1.4%)

1 (1.4%)

0

0

1 (1.4%)

 

9 (22%)

20 (49%)

5 (12%)

0

3 (7.3%)

3 (7.3%)

1 (2.4%)

0

 0.027

Most reactions experienced by patients were low grade (≤ grade 2) across all cohorts (cimetidine 100%, famotidine 98.5%, nizatidine 100%, ranitidine 98.3%, no H2 antagonist 98.9%). 

Multivariable logistic regression model demonstrated no association between H2 antagonist strategy employed and the incidence of a HSR (odds ratio 1.04; 95% confidence interval 0.65 to 1.66; p= 0.09). 

Adverse Events

 See results 

Study Author Conclusions

Results presented within the study are consistent with other recently published evidence to suggest that H2antagonists do not confer any advantage as part of premedication regimens in reducing the incidence of HSR in patients treated with paclitaxel.

InpharmD Researcher Critique

The study reported variability in specific H2 antagonists being used in the premedication regimen, suggesting the ineffectiveness is a class effect; however, there was no division between different agents associated with HSRs. Further studies are required to illustrate the relationship between the dosing regimen of paclitaxel and the incidence of HSR with or without H2 antagonists. 



References:

Foreman E, Polwart C, Walker A, Chambers P. Histamine-2 (H2) antagonists can be safely removed from standard paclitaxel premedication regimens [published online ahead of print, 2022 Apr 25]. Br J Clin Pharmacol. 2022;10.1111/bcp.15363. doi:10.1111/bcp.15363

 

Hypersensitivity reaction to paclitaxel: a retrospective analysis on the non-inferiority of oral famotidine to intravenous ranitidine in premedication regimen

Design

Retrospective, multicenter, non-inferiority, historical control cohort study

N= 1,282

Objective

To investigate whether oral famotidine is non-inferior to intravenous (IV) ranitidine as a premedication to prevent paclitaxel-associated hypersensitivity reactions

Study Groups

IV ranitidine (n= 635)

PO famotidine (n= 647)

Inclusion Criteria

Age ≥ 18 years and paclitaxel-naïve, had received all cycles of paclitaxel at the study sites, and had received either IV ranitidine or oral (PO) famotidine as premedication on the day of paclitaxel infusion

Exclusion Criteria

Patients who experienced a change in H2RA premedication during any cycle of paclitaxel, or received the nab-paclitaxel formulation 

Methods

Eligible patients received either IV ranitidine (control group) or PO famotidine (study group) as the premedication on the day of paclitaxel infusion.

Duration

Between August 2018 and December 2020

Outcome Measures

Primary: occurrence of a paclitaxel-induced hypersensitivity reaction (HSR) of any severity during any cycle

Secondary: treatment discontinuation, switch to non-paclitaxel based chemotherapy regimens

Baseline Characteristics

  

IV ranitidine (Control group) (n= 635)

PO famotidine (Study group) (n= 647)

 p-Value  

Age, median (IQR), years

 59 (53 – 67) 59 (52 – 66)  0.544  

Female

476 (75%) 485 (75%) 1.000  

With known drug allergy

Yes

No

 

106 (17%)

529 (83%)

 

79 (12%)

568 (88%)

0.022

 

 

  

Primary cancer type

Breast cancer

Ovarian cancer

Lung cancer

 

196 (31%)

123 (20%)

91 (14%)

 

178 (28%)

116 (18%)

116 (18%)

 

0.189

0.508

0.080

  

Chemotherapy regimens

Number of cycles received, median (IQR)

Frequency

Weekly

2-weekly

3-weekly

4-weekly

Dose

< 100 mg/m2

≥ 100 mg/m2

 

5 (3–6)

 

121 (19%)

22 (4%)

489 (77%)

3 (0%)

 

126 (20%)

509 (80%)

 

5 (3–6)

 

107 (17%)

24 (4%)

513 (79%)

3 (0%)

 

114 (18%)

533 (82%)

 

0.094

 

0.239

0.814

0.323

1.000

0.308

 

  

Premedication regimens

Steroid

Standard-dose

Low-dose

H1RA

Chlorpheniramine

Diphenhydramine

H2RA

Ranitidine 50 mg

Famotidine 40 mg

Famotidine 60 mg

 

 

410 (65%)

225 (35%)

 

335 (53%)

300 (47%)

 

635 (100%)

-

- 

 

 

412 (64%)

235 (36%)

 

337 (52%)

310 (48%)

 

-

145 (22%)

502 (78%) 

 

0.740

 

 

0.810

 

 

 

- 

 

  

Results

Endpoint

IV ranitidine (Control group) (n= 635)

PO famotidine (Study group) (n= 647)

Absolute risk difference (95% CI)

Non-inferiority one-sided p-Value

Occurrence of HSR

By premedication

Steroid

Standard-dose

Low-dose

H1RA

Chlorpheniramine

Diphenhydramine

H2RA

Ranitidine 50 mg

Famotidine 40 mg

Famotidine 60 mg

 

 

 

46 (11%)

59 (26%)

 

45 (13%)

60 (20%)

 

105 (17%)

-

- 

 

 

 

48 (12%)

73 (31%)

 

63 (19%)

58 (19%)

 

-

12 (8%)

109 (22%)

 

 

 

+0.4% (-3.97 to +4.83)

+4.8% (-3.44% to 13.0%)

 

+5.3% (-0.295% to +10.9%)

-1.3% (-7.60% to +4.99%)

 

-

-8.3% (-13.0% to -2.08%)

+5.2% (+0.599% to +9.86%)

 

 

 

0.021c

0.485

 

0.537

0.025c

 

-

<0.001c

0.530 

Treatment discontinuation

All causes

Due to HSR to paclitaxel

 

227 (36%)

25 (4%)

 

242 (37%)

13 (2%)

 

+1.7% (-3.62% to + 6.92%)

-1.9% (-3.94% to -0.0726%) 

 

0.731

0.021c

Switch to non-paclitaxel based chemotherapy regimens

All causes

Due to HSR to paclitaxel

 

109 (17%)

21 (3%)  

 

90 (14%)

12 (2%)

 

-3.3% (-7.25% to +0.713%)

-1.5% (-3.34% to +0.294%)

 

0.054

0.050

c. Statistically significant. Non-inferiority one-sided p was significant below 0.025, two-sided p was significant below 0.05.

A separate post-hoc analysis showed that using oral famotidine did not have significant effects on HSR occurrence compared to IV ranitidine (reference) (odds ratio 1.14; 95% CI, 0.85 to 1.53; p= 0.395).

Adverse Events

See Results 

Study Author Conclusions

We found no statistically significant differences in the hypersensitivity reaction rates between intravenous ranitidine and oral famotidine. Oral famotidine was not found to be non-inferior to intravenous ranitidine as a paclitaxel premedication based on the pre-defined non-inferiority margin. The use of oral famotidine with standard-dose steroid as premedication may provide better protection against hypersensitivity reactions.

InpharmD Researcher Critique

This retrospective analysis had treatment groups studied in a historical succession rather than simultaneously, proving the causation of any effects difficult. Other baseline variables (e.g., patients with atopy, a history of mild skin reaction sin earlier treatments, respiratory dysfunction, postmenopausal stats, or obesity) that could influence the outcomes of HSR were not evaluated.



References:

Tsoi TT, Young WM, Cheung YT, et al. Hypersensitivity Reaction to Paclitaxel: A Retrospective Analysis on the Non-Inferiority of Oral Famotidine to Intravenous Ranitidine in Premedication Regimen. In Review; 2022. doi: https://doi.org/10.21203/rs.3.rs-1280524/v1