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Raltegravir

Classification: A

Drug products: ISENTRESS

ATC code: J05AX08

Substances: raltegravir, raltegravir potassium

Summary

No differences between men and women in pharmacokinetic properties or effect of raltegravir have been reported. Smaller observational studies have shown gastrointestinal adverse events to be more common in women and muscular symptoms and creatinine phosphokinase elevation more common in men.
 
In our opinion, the described differences do not motivate differentiated dosing or treatment in men and women.

Additional information

Antiretrovirals for treatment of HIV are always given as a combination of at least three medicines. Cobicistat is used to boost the effect of other antiretroviral drugs. As studies on HIV patients always include patients receiving combination therapy it is difficult to know which of the studied medicines that cause changes in effect and/or adverse events.

Pharmacokinetics and dosing

The producer reports no differences between men and women in pharmacokinetic variables and does not recommend differences in dosing according to patient’s sex [1]. In a multicenter, open-label one arm study of raltegravir in HIV patients (109 men, 97 women) pharmacokinetic variables were similar in men and women [2].

Effects

No sex differences were found in an Italian observational cohort study of determinants of virological failure in triple-class experienced patients receiving raltegravir-based regimens (69 men, 32 women) [3]. Similarly, in a multicenter, open-label one arm study of raltegravir in HIV patients (109 men, 97 women) virologic response was found to be similar in men and women [2].

Adverse effects

In the multicenter study of raltegravir in HIV patients mentioned above (109 men, 97 women) drug-related clinical adverse events were more common in women compared to men (18% women, 8% men) and more common in black women compared to non-black women. The difference between men and women was largely attributable to various gastrointestinal adverse events which were more common in women (10% vs 6% in men) [2].

The risk of muscular symptoms and creatinine phosphokinase (CPK) elevation as an adverse effect of raltegravir was studied in a prospective multicenter observational study (333 men, 163 women) of whom 21% had CPK increase. Women had a lower risk of CPK increase than men [4].

Reproductive health issues

Regarding teratogenic aspects, please consult the Drugs and Birth Defects Database (in Swedish, Janusmed fosterpåverkan).

Other information

In a multicenter, open-label one arm study of raltegravir in HIV patients (109 men, 97 women) the discontinuation rate was higher in women (18% vs 13% in men) [2].

A review has described drug exposure in the genital tract of men and women which is of interest in viral transferal and in effect of pre-exposure prophylactic treatment. In men, concentrations in seminal fluid were described to be highest for nucleoside analogues and lowest for protease inhibitors and efavirenz. Seminal accumulation of raltegravir and maraviroc was defined as moderate. The rank order of accumulation presented in the review is nucleoside/nucleotide reverse transcriptase inhibitors [lamivudine/zidovudine/tenofovir/didanosine > stavudine/abacavir] > raltegravir > indinavir/maraviroc/nevirapine >> efavirenz/protease inhibitors [amprenavir/atazanavir/darunavir > lopinavir/ritonavir > saquinavir] > enfuvirtide. In the female genital tract, the nucleoside analogues also were described as having high accumulation ratios, whereas protease inhibitors have limited penetration; however, substantial variability exists. Second generation non-nucleoside reverse transcriptase inhibitor etravirine, and maraviroc and raltegravir, have been found to demonstrate effective accumulation in cervicovaginal secretions. The rank of accumulation presented in the review is nucleoside/nucleotide reverse transcriptase inhibitor [zidovudine/lamivudine/didanosine > emtricitabine/tenofovir] > indinavir > maraviroc/raltegravir/darunavir/etravirine > nevirapine/abacavir > protease inhibitors [amprenavir/atazanavir/ritonavir] > lopinavir/stavudine/efavirenz > saquinavir [5].

Updated: 2019-02-26

Date of litterature search: 2018-07-18

References

  1. Isentress (raltegravir). Summary of Product Characteristics. European Medicines Agency (EMA); 2018.
  2. Squires KE, Bekker LG, Eron JJ, Cheng B, Rockstroh JK, Marquez F et al. Safety, tolerability, and efficacy of raltegravir in a diverse cohort of HIV-infected patients: 48-week results from the REALMRK Study. AIDS Res Hum Retroviruses. 2013;29(6):859-70. PubMed
  3. Bucciardini R, D'Ettorre G, Baroncelli S, Ceccarelli G, Parruti G, Weimer LE et al. Virological failure at one year in triple-class experienced patients switching to raltegravir-based regimens is not predicted by baseline factors. Int J STD AIDS. 2012;23(7):459-63. PubMed
  4. Madeddu G, De Socio GV, Ricci E, Quirino T, Orofino G, Carenzi L et al. Muscle symptoms and creatine phosphokinase elevations in patients receiving raltegravir in clinical practice: Results from the SCOLTA project long-term surveillance. Int J Antimicrob Agents. 2015;45(3):289-94. PubMed
  5. Else LJ, Taylor S, Back DJ, Khoo SH. Pharmacokinetics of antiretroviral drugs in anatomical sanctuary sites: the male and female genital tract. Antivir Ther. 2011;16(8):1149-67. PubMed
  6. Läkemedelsstatistik. Stockholm: Socialstyrelsen. 2017 [cited 2018-07-24.] länk

Authors: Mia von Euler, Linnéa Karlsson Lind

Reviewed by: Karin Schenck-Gustafsson

Approved by: Karin Schenck-Gustafsson