Download Zofran Subcutaneous Pump in the Treatment of Hyperemesis

Clinical Policy Title: Zofran Subcutaneous Pump in the Treatment of Hyperemesis
Gravidarum
Clinical Policy Number: 12.02.02
Effective Date:
Initial Review Date:
Most Recent Review Date:
Next Review Date:
June 1, 2014
February 19, 2014
March 19th, 2014
February, 2014
Policy contains:
 Zofran Subcutaneous Pump
 Hyperemesis Gravidarum
treatment
ABOUT THIS POLICY: AmeriHealth Caritas has developed clinical policies to assist with making coverage determinations. AmeriHealth Caritas
clinical policies are based on guidelines from established industry sources such as Centers for Medicare and Medicaid (CMS), State regulatory
agencies, the American Medical Association (AMA), medical specialty professional societies, and peer reviewed professional literature. These clinical
policies, along with other sources, such as plan benefits and state and federal laws and regulatory requirements, including any state or plan specific
definition of “medically necessary”, and the specific facts of the particular situation are considered by AmeriHealth Caritas when making coverage
determinations. In the event of conflict between this clinical policy and plan benefits and/or state or federal laws and/or regulatory requirements,
the plan benefits and/or state and federal laws and/or regulatory requirements shall control. AmeriHealth Caritas clinical policies are for
informational purposes only and not intended as medical advice or to direct treatment. Physicians and other health care providers are solely
responsible for the treatment decisions for their patients. AmeriHealth Caritas clinical policies are reflective of evidence based medicine at the time
of review. As medical science evolves, AmeriHealth Caritas will update its clinical policies as necessary. AmeriHealth Caritas clinical policies are not
guarantees of payment.
Coverage Policy:
AmeriHealth Caritas considers the use of Zofran via subcutaneous microinfusion pump to be clinically
proven for the treatment of Hyperemesis Gravidarum during pregnancy and therefore, medically necessary
when all of the following criteria are met:
A. Hyperemesis Gravidarum is diagnosed after nine weeks of gestation. AND
B. All other causes of nausea and vomiting have been ruled out. AND
C. Evidence of persistent vomiting, weight loss of more than 5%. AND
D. Documentation of one of the following: ketouria, hypokalemia, high urine specific gravity
(dehydration). AND
E. All other pharmacologic treatment has been attempted and failed, which include;
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1. Prochlorperazine (Compazine IM/PO. OR
2. Trimethobenzamide (Tigan PR). OR
3. Promethazine (Phenergan IM/PO/PR). OR
4. Metoclopramide (Reglan PO). OR
5. Ondansetron (Zofran PO). AND
F Either intravenous metoclopramide (Reglan) or intravenous ondansetron (Zofran) must have been
attempted and failed.
Limitations: All other uses of for Zofran Subcutaneous microinfusion pumps are not medically necessary.
Alternative Covered Services:
 Nutritional counseling, IV hydration, physician office visits.
Background:
Infusion pumps are used for many clinical applications, including intravenous, epidural, and subcutaneous
delivery of analgesic and anesthetic, antibiotics, cardiovascular drugs, antiemetic and insulin. Drug delivery
via infusion reduces the plasma drug concentration fluctuation associated with oral delivery and the slow
onset and long depot effect associated with transdermal patch delivery. Infusion pumps are commonly
used with continuous, intermittent or pulsatile delivery of drug is needed. They also provide an alternative
for patients intolerant to oral administration and can be programmed to achieve special delivery profiles.
Recently, a compact, disposable drug delivery device that incorporates a relatively short, 5-mm-long
hypodermic needle has been shown to continuously and subcutaneously infuse drug solutions. This type of
device can be worn on the skin in a discrete and convenient manner and deliver drug from a pressuredriven reservoir through the needle into the skin. Micro needles can be coupled with a micropump to make
a wearable infusion device that is highly patient friendly and can serve as a potential replacement for
conventional hypodermic needles and infusion sets. Microneedles are expected to be safe because they
are minimally invasive devices that are inserted only into skin’s superficial layers and are typically bloodless
and painless.
In the mid-eighties, continuous subcutaneous antiemetic therapy was widely employed in clinical practice
for treating nausea and vomiting during pregnancy despite the dearth of published clinical evidence to
support the intervention. At that time, physicians began prescribing continuous subcutaneous
metoclopramide (Reglan) via a portable, programmable Micro-infusion pump (MiniMed 404SP-MiniMed
Technologies, Sylmar, Ca.) called the Reglan pump. In the late nineties, after ondansetron (Zofran) was
widely promoted as an anti-emetic for patients with chemotherapy-induced nausea and vomiting,
obstetricians began prescribing it in much the same way as had been done a decade earlier with
metoclopramide. This became commonly referred to as a Zofran Pump.
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Nausea and vomiting of pregnancy, commonly known as “morning sickness,” affects approximately 80 percent
of pregnant women. Nausea and vomiting of pregnancy is generally a mild, self-limited condition that may be
controlled with conservative measures. A small percentage of pregnant women have a more profound course,
with the most severe form being Hyperemesis Gravidarum. Unlike morning sickness, Hyperemesis Gravidarum
may have negative implications for maternal and fetal health. Guidelines suggest that Physicians carefully
evaluate patients with non-resolving or worsening symptoms to rule out the most common pregnancy-related
and non-pregnancy related causes of severe vomiting. Once pathologic causes have been ruled out, treatment
is individualized alternative therapies such as ginger or acupressure are still under investigation. Women with
more complicated nausea and vomiting of pregnancy also may need pharmacologic therapy. Several
medications have been shown to be safe and effective treatments. If oral and intravenous administrations
prove inadequate, subcutaneous drug microinfusion may be necessary.
Hyperemesis Gravidarum is the most severe form of nausea and vomiting in pregnancy, characterized by
persistent nausea and vomiting associated with ketosis and weight loss (>5% of prepregnancy weight). This
condition may cause volume depletion, electrolytes and acid-base imbalances, nutritional deficiencies, and
even death. Severe Hyperemesis requiring hospital admission occurs in 0.3-2% of pregnancies.
Adverse Fetal and Maternal Outcomes from Hyperemesis Gravidarum
Women with uncomplicated nausea and vomiting of pregnancy (“morning sickness”) have been noted to have
improved pregnancy outcomes, including fewer miscarriages, preterm deliveries, and stillbirths, as well as
fewer instances of fetal low birth weight, growth retardation, and mortality. In contrast, Hyperemesis
Gravidarum has been associated with increases in maternal adverse effects, including splenic avulsion,
esophageal rupture, Mallory-Weiss tears, pneumothorax, peripheral neuropathy, and preeclampsia, as well as
increases in fetal growth restriction and mortality.
Pharmacologic approaches for the treatment of Nausea and Vomiting during Pregnancy (NVP) have been
based on the pathophysiology of nausea and vomiting, and on treatments found to be successful for nonpregnant subjects. Potential treatments include antihistamines, anticholinergics, dopamine antagonists, 5HT3 antagonists, corticosteroids, cisapride, and cannabinoids.
METHODS
Searches:
We searched PubMed and the databases of:
 UK NHS Centre for Reviews and Dissemination;
 AHRQ guideline clearinghouse and evidence-based practice centers; and
 Centers for Medicare and Medicaid Services.
Searches were conducted January 2014 using the terms “Zofran, Infusion Pump” and” Nausea and
Vomiting”. We included:
 Systematic reviews, which pool results from multiple studies to achieve larger sample sizes and greater
precision of effect estimation than in smaller primary studies. Systematic reviews use pre-determined
transparent methods to minimize bias: effectively treating the review as a scientific endeavor, thus are
rated highest in evidence grading hierarchies;
 Guidelines based on systematic reviews; and
 Economic analyses: cost-effectiveness, -benefit or -utility studies, which report both costs and
outcomes; (but not simple cost studies), sometimes referred to as efficiency studies, also rank near the
top of evidence hierarchies.
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Findings
Research has shown that the initial treatment preferred, is conservative and involves dietary changes and
emotional support. Vitamin B6 and doxylamine (are recommended by the American College of Obstetrician
and Gynecologists (ACOG) as the first-line therapy for nausea and vomiting in pregnancy. The entire body of
evidence involving continuous subcutaneous anti-emetic therapy for treatment of nausea and vomiting
during pregnancy consists of five industry sponsored and authored nonrandomized reports. These
therapies do not appear, based on published payment levels, to be cost-effective when compared to
conventional treatment alternatives including episodic hospitalization (Reichmann, 2008). Managed care
organizations that design evidence based clinical coverage guidelines may want to limit the use to
extremely recalcitrant cases of Hyperemesis Gravidarum until sufficiently powered, independent,
randomized, controlled trials demonstrate clinical efficacy and cost-effectiveness.
Summary of Clinical Evidence
Citation
Content, Methods, Recommendations
Naef RW, III., et
al (1995)
Our objective was to determine whether medical therapy in the home
for patients with Hyperemesis Gravidarum is safe, efficacious, and cost
effective compared with hospitalization. In this retrospective, matched
control study 50 women with Hyperemesis were treated in the home
and were matched for gravidity, gestational age, and weight loss from
prepregnancy weight with 47 patients who were hospitalized for
traditional treatment. Both groups had similar intravenous fluid and
medical support until they could tolerate adequate oral intake. Women
in the home had 9.7 +/- 8.0 days of intravenous therapy compared with
9.5 +/- 6.2 days in hospitalized patients (not significant). The mean
percent of weight loss at initiation of therapy was similar in both groups
(4.6% +/- 5.7% vs 4.5% +/- 6.1%, not significant). The mean weight
change during therapy in the home group was + 1.0 +/- 4.3 pounds
compared with +1.2 +/- 8.6 pounds in the hospitalized group (not
significant). The only complication was infiltration of the intravenous
site, the occurrence of which was similar in the two groups (40% vs.
57%, not significant). At discontinuation of therapy 90% of the home
patients no longer required any supportive therapy; 10% (n = 5)
required hospitalization because of relapse. The cost of therapy was
significantly lower for patients in the home group ($708 +/- $533 vs
$2701 +/- $1717, p < 0.001). These data show that management of
Hyperemesis in the home is safe. Furthermore, successful therapy can
be achieved in the home at a significantly reduced cost.
Buttino, L. et al
(200)
OBJECTIVE: To describe the use of subcutaneous (s.c.)
metoclopramide in the outpatient treatment of Hyperemesis
Gravidarum. STUDY DESIGN: In a retrospective design, women who
received continuous s.c. metoclopramide for treatment of Hyperemesis
Gravidarum were identified from a national database. Data analysis
included weight at start and stop of treatment, frequency of resolution
of symptoms, and side effects of medication. In addition, data were
collected on adjuvant therapies. RESULTS: Between January and
December of 1997, there were 646 women with Hyperemesis
Gravidarum who received continuous s.c. metoclopramide on an
outpatient basis. A total of 413 patients (63.9%) had complete
resolution of symptoms. Seventy-five percent of patients had received
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one or more antiemetic medications before initiation of s.c.
metoclopramide. A total of 192 patients (30.5%) reported at least one
side effect related to treatment. The majority of reported side effects
was considered mild and did not require discontinuation of s.c.
metoclopramide. CONCLUSION: S.c. metoclopramide appears to be a
safe, effective treatment for Hyperemesis Gravidarum. Outpatient
treatment may result in decreased costs compared with inpatient
hospitalization.
Glossary:
Emetogenic- Having the capacity to induce emesis (vomiting), a common property of anticancer agents,
narcotics and morphine.
Hyperemesis Gravidarum (HG) - Severe nausea and vomiting during pregnancy that can lead to loss of
weight and body fluids.
Infusion Pump-A medical device that delivers fluids, such as nutrient, and medications, into a person’s a
body in controlled amounts. Infusion pumps are in widespread use in clinical settings such as hospitals, and
in the home.
Medically Necessary- A service or benefit is Medically Necessary if it is compensable under the MA
Program and if it meets any one of the following standards:



The service or benefit will, or is reasonably expected to, prevent the onset of an illness, condition or
disability.
The service or benefit will, or is reasonably expected to, reduce or ameliorate the physical, mental
or developmental effects of an illness, condition, injury or disability.
The service or benefit will assist the Member to achieve or maintain maximum functional capacity
in performing daily activities, taking into account both the functional capacity of the Member and
those functional capacities that are appropriate for Members of the same age.
Microinfusion pump-Microinfusion pumps (MIPs) are used to administer medications at low infusion rates
and for chemotherapy and analgesia.
NVP-Nausea and Vomiting of Pregnancy
Ondansetron (Zofran) is a selective 5-hydroxytryptamine (3) (5-HT (3)) receptor antagonist that has been
introduced to clinical practice as an antiemetic for cancer treatment-induced and anesthesia-related
nausea and vomiting. Its use under these circumstances is both prophylactic and therapeutic.
S.C.-Subcutaneous
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Related Policies: AmeriHealth Caritas Utilization Management Program Description
REFERENCES
Professional Society Guidelines
1. ACOG Practice Bulletin. Clinical Management Guidelines for Obstetric-Gynecologists. Nausea and
vomiting of pregnancy. Obstetrics and Gynecology 2004; 103(4):803-14.
2. Goodwin TM. Hyperemesis Gravidarum. Clinical Obstetrics and Gynecology 1998; 41(3):597-605.
3. Bailit JL. Hyperemesis gravidarium: Epidemiologic findings from a large cohort. American Journal of
Obstetrics and Gynecology 2005; 193(3 Pt 1):811-4.
4. National Hospital Discharge Database Analysis, all payers, all applicable states, 2003-2004.
5.
GlaxoSmithKline Research Triangle Park, NC 27709 ©2013, GlaxoSmithKline. ZFJ: 8PI
Peer-Reviewed References
1. Naef RW, III, et al. Treatment for Hyperemesis Gravidarum in the home: an alternative to
hospitalization. Journal of Perinatology 1995; 15(4):289-92.
2. Buttino L, et al. Home subcutaneous metoclopramide therapy for Hyperemesis Gravidarum. Journal
of Perinatology 2000; 20(6):359-62.
3. Spruill SC, Kuller JA. Hyperemesis Gravidarum complicated by Wernicke's encephalopathy. Obstetrics
and Gynecology 2002; 99(5 Pt 2):875-7.
4. McCullough SG, Chronis Kuhn JP, Peskin E. One HMO's experience with the management of
Hyperemesis Gravidarum. HMO Practice 1996; 10(3):143-5.
5. Yost NP, et al. A randomized, placebo-controlled trial of corticosteroids for Hyperemesis due to
pregnancy. Obstetrics and Gynecology 2003; 102(6):1250-4.
6. James P. Reichmann, MBA Michael S. Kirkbride, BSc, Pharm D Reviewing the Evidence for Using
Continuous Subcutaneous Metoclopramide and Ondansetron to Treat Nausea & Vomiting During
Pregnancy.
7. Laura A. Magee, MD, FRCPC, MSClinEpidemiol/CommH, The Safety and Effectiveness of Antiemetic
Therapy for NVP.
8. C A Sullivan; C A Johnson; H Roach; Rick W. Martin; D.K. Stewart; John Morrison American journal of
obstetrics and gynecology 1996;174(5):1565-8.
9. Ziaei S, Hosseiney FS, Faghihzadeh S. The efficacy low dose of prednisolone in the treatment of
Hyperemesis Gravidarum. Acta Obstetricia et Gynecologica Scandinavica 2004; 83(3):272-5.
10. Jennifer R. Niebyl, Nausea and Vomiting in Pregnancy; The New England Journal of Medicine,
2010:363:1544-50.
Clinical Trials
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A. Reviewing the evidence for using continuous subcutaneous metoclopramide and ondansetron to
treat nausea & vomiting during pregnancy.
OBJECTIVE: To examine the medical evidence regarding the clinical efficacy and costeffectiveness of the application of continuous subcutaneous metoclopramide and ondansetron
to treat nausea and vomiting during pregnancy. STUDY DESIGN: All of the published peerreviewed articles on the subject were assembled and assigned a level of evidence based on
research design. The search uncovered one level II matched, controlled trial and three level III
uncontrolled, retrospective case series published in peer review journals, as well as a book
chapter. The book chapter, although not subjected to the peer-review process, is included in
this review due to the paucity of other evidence. RESULTS: The matched cohort trial showed
that continuous subcutaneous metoclopramide is significantly less-tolerated than continuous
subcutaneous ondansetron (31.8% vs. 4.4%; P < 0.001). The four case series reported complete
symptom resolution for 63.9% to 75% of the patients. Complications arose in 24.9% to 30.5% of
the selected cases that were severe enough to require discontinuation of therapy.
Complications included side effects of a worsening of symptoms. All of the trials are
retrospective and observational in nature and, therefore, subject to the limitations inherent in
the research design. Absent the benefit of meaningful cohort controls, comparative statements
effectiveness cannot be substantiated with the available data. CONCLUSION: Randomized,
controlled trials of sufficient power are necessary before long-term continuous subcutaneous
metoclopramide or ondansetron can be used on a widespread basis to treat nausea and
vomiting during pregnancy. Cost approximations in the case series are reported and, when
compared to the cost of other methods of treatment previously published in the medical
literature, the therapy appears to be cost-prohibitive. However, definitive statements cannot
be made regarding cost-effectiveness until clinical efficacy is demonstrated through a
sufficiently powered, well-designed, randomized control trial (RCT). Until such time, the
therapy should remain experimental and coverage is restricted to intractable Hyperemesis
Gravidarum (HG) that is unresponsive to more-conventional treatment options.
B. Reviewing the Evidence for Using Continuous Subcutaneous Metoclopramide and Ondansetron
to Treat Nausea & Vomiting During Pregnancy. (James P. Reichmann, MBA; Michael S. Kirkbride,
BSc, Pharm.
EVIDENCE REVIEW- The published medical evidence on continuous subcutaneous antiemetic
therapy consists of one level II retrospective non-randomized matched cohort study, four level III
uncontrolled retrospective descriptive case series, three published peer reviewed articles, and a
book chapter (Table 1). No comparative trials containing conventional lower-cost treatments as
controls have been published to date.
Table1
Continuous subcutaneous anti-emetic pump evidence
Study
N
Research
Level of
Symptom
Symptom
Failed
Side effect rate
7
design
evidence
resolution
improvement
therapy
Buttino
1998
301
Case
series
III
195
(64.8%)
-
91
(30.1%)
164 (54.5%)
Buttino
2000a
646
Cases
series
III
413
(63.9%)
-
NR
192
Buttino
2000b
11541
Cases
series
III
N/A
N/A
N/A
N/A
Lombardi
20042
428
Cases
series
III
382 (89.3%)
NR
167 (39%)
Klauser
2011
355 –
CSMT3
521CSOT3
Matched
cohort
II
NR
NR
31.8%
4.4%
NR
NR
68.2%
95.8%
N/A, not applicable; NR, not reported.
1947 (82.1%) of the patients were previously reported in the first two trials.
2Included patients receiving subcutaneous metoclopramide as well as patients moved to continuous
subcutaneous ondansetron. Reported results rendered continuous subcutaneous ondansetron outcomes
indiscernible.
3CSMT = Continuous subcutaneous metoclopramide and CSOT = Continuous subcutaneous ondansetron.
Centers for Medicare and Medicaid Services (CMS) National Coverage Determination
 Guidance, Pub. 100-03, Chapter 1, Part 4, Section 280.14
Effective Date: November 27, 2006
Implementation Date: November 27, 2006
The NCD for infusion pumps at section 280.14 sets forth specific coverage criteria under sections A-D.
Under section B.1.f other uses of external infusion pumps are covered if the contractor’s medical staff
verifies the appropriateness of the therapy and the prescribed pump for the individual beneficiary.
Local Coverage Determinations
None found as of this writing.
Commonly Submitted Codes:
Below are the most commonly submitted codes for the service(s)/item(s) subject to this policy. This is not
an exhaustive list of codes. Providers are expected to consult the appropriate coding manuals and bill in
accordance with those manuals.
CPT Code
Description
99601
Home infusion/specialty drug administration, per visit ( up to 2
Hours) each additional hour
99602
Each additional hour
Comment
List separately in
addition to code for
primary procedure
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ICD-9 Code
Description
643.00
Mild Hyperemesis Gravidarum; starting after nine (9) weeks of
gestation
643.01
Mild Hyperemesis Gravidarum, delivered, with or without
mention of antepartum condition
643.03
Mild Hyperemesis Gravidarum, antepartum condition or
complication
643.10
Hyperemesis Gravidarum with metabolic disturbance,
unspecified as to episode of care or not applicable
643.11
Hyperemesis Gravidarum with metabolic disturbance, delivered,
with or without mention of antepartum condition
643.13
Hyperemesis Gravidarum with metabolic disturbance,
antepartum condition or complication
ICD-10
Code
Description
021.0
Mild Hyperemesis Gravidarum
021.1
Hyperemesis Gravidarum with metabolic disturbance
HCPCS
Level II
Description
J2405
Injection, Injection,(Zofran) ondansetron hydrochloride, per 1 mg
J2765
Injection, Reglan (metoclopramide HCl), up to 10 mg
E0779
Ambulatory infusion pump, mechanical, reusable, for infusion 8
hours or greater
E0780
Ambulatory infusion pump, mechanical, reusable, for infusion
less than 8 hours
E0781
Ambulatory infusion pump, single or multiple channels, electric
or battery operated, with administrative equipment, worn by
patient
S9351
Comment
Comment
Comment
Home infusion therapy, continuous or intermittent antiemetic
infusion therapy; administrative services, professional pharmacy
services, care coordination, and all necessary supplies and
equipment (drugs and nursing visits coded separately), per diem
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