DMPA use and fracture risk: an update - … use and fracture risk: an update 1 ... is available on slides 8-9. ... injection during the first 5 days of a normal menstrual cycle

$Page 1: DMPA use and fracture risk: an update - … use and fracture risk: an update 1 ... is available on slides 8-9. ... injection during the first 5 days of a normal menstrual cycle$
PP-DEP-GBR-0026 January 2017

DMPA use and fracture risk:

an update

1

Prescribing Information and adverse event reporting for Depo-Provera®

(Medroxyprogesterone Acetate) is available on slides 8-9


DMPA, medroxyprogesterone acetate; UK, United Kingdom.

1. Lanza LL, et al. Obstet Gynecol 2013;121:593–600.

The Lanza study design

• A retrospective, non-randomised, cohort study of 312,395 women using UK

population-based data from the General Practice Research Database1

• Women aged 15–50 years of age at the first contraceptive prescription were

included1

• A subcohort of 166,367 women had baseline data available for the 6 months

before the first prescription

• All incident fractures were included; fracture incidence and risk factors

before starting contraceptive use (DMPA or other) were estimated1

• Fracture incidence was estimated before and after the start of

contraceptive use for DMPA users and non-users1

2

Main objective: to analyse fracture incidence in users of DMPA and users of other

hormonal contraceptives before and after the start of contraceptive use1


CI, confidence interval; DMPA, medroxyprogesterone acetate; IRR, incidence rate ratio.


Fracture rate before and after the first

DMPA injection

• In the subcohort, DMPA users were found to have a higher incidence of

fractures than non-users before the first DMPA injection at Day 1 (crude IRR

1.28) as well as after the start of contraception (crude IRR 1.23)1

• There was no clinically relevant increase in fracture rates in either group

after starting contraception1

3

Fracture rate/1000 person-years Crude IRR (95% CI)DMPA use/non-use

Non-DMPA users (n=124,491)

DMPA users (n=41,876)

Before treatment 6.6 8.4 1.28 (1.07–1.53)

After first treatment 7.3 9.1 1.23 (1.16–1.30)

IRR (95% CI) After/before 1.12 (1.01–1.24) 1.08 (0.92–1.26)



* IRR adjusted for age and risk factor for DMPA use during the study period compared with non-use of DMPA.

†Incident rate ratios are standardised for age in 5-year groups and for each factor (one at a time).


No other risk factors were identified

Potential confounding

factors

Proportion of person-years in exposure categories IRR by presence of

risk factor (yes or no)

Adjusted IRR

(95% CI)*DMPA user DMPA non-user

Total person-years 173,713 744,242 - -

Past fracture, any site† 0.0039 0.0029 4.9 1.41 (1.32–1.50)

Alcohol abuse or

dependence0.0014 0.0007 3.8 1.41 (1.32–1.49)

Drug abuse 0.0012 0.0004 2.9 1.40 (1.32–1.48)

Inflammatory bowel disease 0.0010 0.0007 2.1 1.40 (1.32–1.48)

Epilepsy 0.0020 0.0010 2.0 1.40 (1.32–1.48)

Asthma 0.0212 0.0153 1.6 1.39 (1.31–1.48)

Oral corticosteroid therapy 0.0098 0.0074 1.4 1.40 (1.32–1.49)

Baseline fall 0.0043 0.0024 1.4 1.40 (1.32–1.49)

Oestrogen replacement 0.0022 0.0059 1.4 1.40 (1.32–1.49)

Smoking, current 0.1851 0.1092 1.3 1.39 (1.31–1.47)

Pregnancy, age <20 years 0.1103 0.0755 1.2 1.40 (1.32–1.49)

4

• In the subcohort, age was not found to be a confounding factor1

• Adjusted IRRs for fracture in DMPA users versus non-users were similar to the

crude IRR (1.41) indicating a lack of confounding by the factors investigated1




Fracture rate and the number of DMPA

injections

• In the full cohort , compared with non-users of DMPA, the fracture rate was

greater in low-exposure DMPA users (1–7 injections) than in high-exposure

DMPA users (≥8 injections)

• When fracture site was analysed, DMPA users had no excess risk for axial

fractures compared with non-users

5

Number of DMPA injections

Fracture rate/1000 person-years*

Crude IRR (95% CI)

0 (non-users)† 6.4 1.00

1–7 (low exposure) 9.4 1.47 (1.40–1.54)

≥8 (high exposure) 7.8 1.22 (1.13–1.32)

*Age-standardised rates (not shown) are not different from the crude rates.

†Non-exposure includes person-years of never-users and person-years of DMPA users before first DMPA prescription.


DMPA, medroxyprogesterone acetate;.


Lanza study: summary of key findings

The higher fracture rate observed in DMPA users compared with non-

users did not appear to be caused by DMPA:1

• DMPA users had a higher fracture rate than non-users before the start of

contraception and on Day 1 of starting contraception

• The fracture rate did not increase after initiation of contraception compared

with before treatment

• In the full cohort, fracture rate in high-exposure DMPA users was less than in

low-exposure users

• In the full cohort, there was no difference in the axial fracture rate between

DMPA users and non-users

6

Although DMPA users had more fractures than non-users, this association might be the

result of confounding by a pre-existing risk for fractures in women who choose DMPA

contraception1


DMPA use and BMD post-menopauseOrr-Walker BJ, et al. 1998

BMD adjusted for weight and age

in post-menopausal women

7

BMD, bone mineral density; DMPA, medroxyprogesterone acetate.

1. Orr-Walker BJ, et al. Clin Endocrinol 1998;49:615–618.

2. Petitti DB, et al. Obstet Gynecol 2000;95:736–744.

Adapted from Orr-Walker et al. 1998.

Me

an

BM

D ±

SE (

g/c

m2)

• Orr-Walker conducted a cross-sectional

study to compare BMD in post-

menopausal former users of DMPA with

non-users (n=346)1

• There was no significant difference in bone

density between former DMPA users and

non-users in post-menopausal women1

• It was the opinion of the investigators that

previous DMPA-use was unlikely to have a

substantial impact on bone fracture risk in

the post-menopausal years1

The Lanza study did not determine if DMPA use during reproductive years

could impact fracture rate post-menopause; however, cross-sectional

studies found BMD in former DMPA users was similar to that of non-users1,2


Depo-Provera 150 mg/ml

(medroxyprogesterone acetate)

ABBREVIATED PRESCRIBING INFORMATION (UK)

Please refer to the SmPC before prescribing

Depo-Provera 150 mg/ml.

Presentation: 1 ml Disposable syringe, containing

150 mg medroxyprogesterone acetate in a

Sterile suspension for injection.

Indication: Long-term contraceptive agent, in

women who have been counselled concerning

the likelihood of menstrual disturbance,

potential delay in return to full fertility and risks of

bone mineral density losses. Short-term

contraception for the following (i) for partners of

men undergoing vasectomy, until the

vasectomy becomes effective, (ii) in women

who are being immunised against rubella (iii) in

women awaiting sterilisation. May only be used

in adolescents (12-18 years) after other methods

of contraception were considered to be

unsuitable.

Dosage: First injection: 150mg intramuscular

injection during the first 5 days of a normal

menstrual cycle. Post Partum: Within 5 days

post-partum if not breast-feeding. Women in

puerperium can experience prolonged and

heavy bleeding, therefore caution is required,

and women should be advised accordingly. If

the puerperal woman will breast-feed, the initial

injection should be no sooner than 6 weeks post

partum. Further doses: These should be given at

12 week intervals, however as long as the

injection is given no later than 5 days after the

12 week interval, no additional contraception

measures are required. For partners of men

undergoing vasectomy, a second injection 12

weeks after the first may be necessary in a small

proportion of patients where the partner's sperm

count has not fallen to zero. If the dose repeat

interval is greater than 89 days (12 weeks and 5

days) for any reason, then pregnancy should be

excluded before the next injection is given and

the patient should use additional contraceptive

measures (e.g. barrier) for fourteen days after

this subsequent injection. Elderly: Not

appropriate. Children: Depo-Provera is not

indicated before menarche. Data in adolescent

females (12-18 years) is available, Refer to the

Summary of Product Characteristics for further

information. Other than concerns about loss of

BMD, the safety and effectiveness of Depo-

Provera is expected to be the same for

adolescents after menarche and adult females.

Depo-Provera may be poorly metabolised in

patients with severe liver insufficiency. No

dosage adjustment is required for renal

insufficiency. Administration: By deep

intramuscular injection. The sterile aqueous

suspension should be vigorously shaken just

before use to ensure the dose being given

represents a uniform suspension.

Contraindications: Known hypersensitivity to

medroxyprogesterone acetate or any of its

excipients. Pregnancy. Known or suspected

hormone-dependent malignancy of breast or

genital organs. Patients with presence or a

history of severe hepatic disease whose liver

function has not returned to normal. Patients

with abnormal uterine bleeding, whether

administered alone or in combination with

oestrogen until a definite diagnosis has been

established and the possibility of genital tract

malignancy eliminated.

Special Warnings and Precautions: Use of Depo-

Provera reduces serum oestrogen levels and is

associated with significant loss of BMD due to

the known effect of oestrogen deficiency on

the bone remodelling system. Bone loss is

greater with increasing duration of use, however

BMD appears to increase after Depo-Provera is

discontinued and ovarian oestrogen production

increases. In adolescents and women with

significant lifestyle and/or medical risk factors for

osteoporosis, other methods of contraception

should be considered before using Depo-

Provera. The administration of Depo-Provera

usually causes disruption of the normal

menstrual cycle. Bleeding patterns can include

amenorrhoea. Women should be counselled

that there is a potential for delay in return to full

fertility following use of the method, regardless

of the duration of use. Long-term case-

controlled surveillance of Depo-Provera users

found no overall increased risk of ovarian, liver,

or cervical cancer and a prolonged, protective

effect of reducing the risk of endometrial

cancer in the population of users. Refer to the

Summary of Product Characteristics for further

information. There is a tendency for women to

gain weight while on Depo-Provera therapy.

Reports of anaphylactic responses

(anaphylactic reactions, anaphylactic shock,

anaphylactoid reactions) have been received.

Should the patient experience pulmonary

embolism, cerebrovascular disease or retinal

thrombosis while receiving Depo-Provera, the

drug should not be re-administered.

8

Depo-Provera® Abbreviated

Prescribing Information slide 1 of 2


Patients with a history of endogenous

depression should be carefully monitored.

Some patients may complain of premenstrual

type depression while on Depo-Provera

therapy. As with any intramuscular injection,

especially if not administered correctly, there is

a risk of abscess formation at the site of

injection, which may require medical and/or

surgical intervention. Patients with a history of

the following conditions should be carefully

monitored: endogenous depression (including

premenstrual-type depression), migraine or

unusually severe headaches, acute visual

disturbances of any kind, pathological changes

in liver function or hormone levels. Diabetic

patients should be carefully monitored while

receiving DMPA; increases and decreases in

total cholesterol, triglycerides and low-density

lipoprotein (LDL) cholesterol have been

observed. DMPA have been associated with a

15-20% reduction in serum high density

lipoprotein (HDL) cholesterol levels. Potential for

an increased risk of coronary disease should be

considered prior to use. Doctors should carefully

consider the use of DMPA in patients with

recent trophoblastic disease before levels of

human chorionic gonadotrophin have returned

to normal. Pathologists should be informed of

the patient's use of Depo-Provera if endometrial

or endocervical tissue is submitted for

examination. Results of certain laboratory tests

may be affected. Refer to the Summary of

Product Characteristics for further information.

Drug interactions: Aminoglutethimide

administered concurrently may significantly

depress bioavailability. The possibility of

interaction (including oral anticoagulants)

should be borne in mind in patients receiving

concurrent treatment with other drugs.

Medroxyprogesterone acetate (MPA) is

metabolized in-vitro primarily by hydroxylation

via the CYP3A4. Specific drug-drug interaction

studies evaluating the clinical effects with

CYP3A4 inducers or inhibitors on MPA have not

been conducted and therefore the clinical

effects of CYP3A4 inducers or inhibitors are

unknown. Pregnancy and Lactation: Check for

pregnancy before initial injection, and also if

administration of subsequent injection is

delayed beyond 89 days (12 weeks and 5

days). Effects on ability to drive and use

machines: Depo-Provera may cause

headaches and dizziness. Patients should be

advised not to drive or operate machinery if

affected. Side-effects: Very common (≥1/10):

nervousness, abdominal pain or discomfort,

headache, weight increased or decreased.

Common (≥1/100 to <1/10):depression, libido

decrease, nausea, abdominal distention,

alopecia, acne, rash, back pain, dizziness, ,

pain in extremity, vaginal discharge, breast

tenderness, dysmenorrhea, genitourinary tract

infection, oedema/fluid retention, asthenia .

Uncommon (≥ 1/1000 to < 1/100): drug

hypersensitivity, increased or decreased

appetite, insomnia, seizure, somnolence,

paraesthesia, hot flush, dyspnoea, hepatic

function abnormal, hirsutism, urticaria, pruritus,

chloasma, dysfunctional uterine bleeding

(irregular, increased, decreased, spotting),

galactorrhoea, pelvic pain, dyspareunia,

suppressed lactation, chest pain. Other side

effects include: breast cancer, anaemia, ,

anaphylactic reaction, anaphylactoid

reaction, angioedema, anorgasmia, emotional

disturbance, affective disorder, irritability,

anxiety, migraine, paralysis, syncope, vertigo,

tachycardia, embolism and thrombosis, deep

vein thrombosis, thrombophlebitis, hypertension,

varicose veins, pulmonary embolism, rectal

haemorrhage, gastrointestinal disorder,

jaundice, hepatic enzyme abnormal,

lipodystrophy acquired, dermatitis, ecchymosis,

scleroderma, skin striae, arthralgia, muscle

spasms, osteoporosis, osteoporotic fractures,

vaginitis, amenorrhoea, breast pain,

metrorrhagia, menometrorrhagia, menorrhagia,

vulvovaginal dryness, breastatrophy, ovarian

cyst, premenstrual syndrome, endometrial

hyperplasia, breast mass, nipple exudate

bloody, vaginal cyst, breast enlargement, lack

of return to fertility, sensation of pregnancy,

pyrexia, fatigue, injection site reaction, ,

dysphonia, VIIth nerve paralysis, axillary swelling,

, glucose tolerance decreased, cervical smear

abnormal.

Refer to the Summary of Product

Characteristics for more detailed information

on side-effects.

Package Quantities and Basic NHS Cost: Single

1ml Syringe pack: £6.01. Legal Category: POM.

Marketing Authorisation Number and Holder: PL

00057/0965, Pfizer Limited, Ramsgate Road,

Sandwich, CT13 9NJ, UK. Last Updated: May

2016

Further information is available on request from:

Medical Information at Pfizer Limited, Walton

Oaks, Dorking Road, Tadworth, Surrey, KT20 7NS,

UK. Tel: +44 (0) 1304 616161

Ref: DP 14_0

9

Depo-Provera® Abbreviated

Prescribing Information slide 2 of 2


Adverse Event Reporting

10

Adverse events should be reported

Reporting forms and information can be found at www.mhra.gov.uk/yellowcard

Adverse events should also be reported to Pfizer Medical Information on 01304 616161

The Yellow Card Scheme is run by the Medicines and Healthcare products Regulatory Agency (MHRA) and Commission on Human Medicines (CHM)

The Scheme is used to collect information from healthcare professionals and the general public on suspected adverse drug reactions (ADRs). The continued success of the Yellow Card Scheme depends on your willingness to report suspected adverse drug reactions

Both healthcare professionals and patients can submit information through the Yellow Card website

Documents

DMPA use and fracture risk: an update - … use and fracture risk: an update 1 ... is available on slides 8-9. ... injection during the first 5 days of a normal menstrual cycle